USE OF MORPHINAN DERIVATIVE FOR THERAPEUTIC TREATMENT OF OPIOID delta RECEPTOR AGONIST-RELATED DISEASE

ABSTRACT

The present invention relates to a pharmaceutical composition comprising a morphinan derivative that exhibits an opioid δ receptor agonist activity. By administering the pharmaceutical composition provided by the present invention, opioid δ receptor related diseases (for example, headache) can be treated or prevented.

TECHNICAL FIELD

The present invention relates to use of a morphinan derivative having anopioid δ receptor agonistic activity, for example, use thereof fortherapeutic treatment of headache.

This application claims convention priority based on Japanese PatentApplication No. 2016-203925 filed on Sep. 16, 2016 in Japan, and theentire disclosures thereof are incorporated into the presentspecification by reference.

BACKGROUND ART

Opioids bind to opioid receptors to exhibit the effect thereof, andthere are three kinds of subtypes of the opioid receptors, i.e., μ, δ,and κ receptors. It is known that agonists of each of the threesubtypes, i.e., μ, δ, and κ, have analgesic effects.

Among them, agonists that selectively activate the opioid δ receptor areexpected not to induce or expected to induce little side effects throughthe activation of the opioid receptor or opioid κ receptor.

Various compounds have so far been reported as opioid δ receptoragonists, and the analgesic activity, antidepressive activity, andanxiolytic activity thereof have been verified (Patent documents 1 to 6and Non-patent documents 1 to 3). As for headache, since it has beendemonstrated that opioid δ receptor agonists are effective for chronicand acute headaches, and they suppress the precursory symptoms ofheadache, they are effective for prophylaxis of headache (Non-patentdocument 4).

PRIOR ART REFERENCES Patent Documents

-   Patent document 1: Japanese Patent Unexamined Publication (Kohyo)    No. 2006-522775-   Patent document 2: WO2001/046192-   Patent document 3: WO2008/001859-   Patent document 4: WO2013/035833-   Patent document 5: WO2014/021273-   Patent document 6: WO2014/136305

Non-Patent Documents

-   Non-patent document 1: Tetrahedron, 2011, 67, 6682-   Non-patent document 2: European Journal of Pharmacology, 276 (1995)    131-135-   Non-patent document 3: European Journal of Pharmacology, 322 (1997)    27-30-   Non-patent document 4: British Journal of Pharmacology, 171 (2014)    2375-2384

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

An object of the present invention is to provide a medicament useful fortherapeutic or prophylactic treatment of opioid δ receptor-relateddiseases (for example, headache).

Means for Solving the Problem

The inventors of the present invention conducted various researches inorder to achieve the aforementioned object. As a result, they found thata pharmaceutical composition comprising a morphinan derivative is usefulfor therapeutic or prophylactic treatment of opioid δ receptor-relateddiseases (for example, headache), and accomplished the presentinvention.

An aspect of the present invention is a pharmaceutical compositioncomprising a compound represented by the following general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

Another aspect of the present invention is to provide a pharmaceuticalcomposition for therapeutic or prophylactic treatment of an opioid δreceptor-related disease (for example, headache), which contains acompound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

Effect of the Invention

A medicament useful for therapeutic or prophylactic treatment of opioidδ receptor-related diseases (for example, headache) is provided by thepresent invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of the mouse elevated plus mazetest for the compound 1. The vertical axis indicates wall-less runningroute staying time ratio, and test compounds and doses thereof are shownunder the horizontal axis.

FIG. 2 is a graph showing the results of the mouse elevated plus mazetest for the compound 7. The vertical axis indicates wall-less runningroute staying time ratio, and test compounds and doses thereof are shownunder the horizontal axis.

FIG. 3 is a graph showing the results of the mouse elevated plus mazetest for the compound 3. The vertical axis indicates wall-less runningroute staying time ratio, and test compounds and doses thereof are shownunder the horizontal axis.

FIG. 4 is a graph showing the results of the mouse elevated plus mazetest for the compound 9. The vertical axis indicates wall-less runningroute staying time ratio, and test compounds and doses thereof are shownunder the horizontal axis.

FIG. 5 is a graph showing the results of the mouse elevated plus mazetest for the compound 10. The vertical axis indicates wall-less runningroute staying time ratio, and test compounds and doses thereof are shownunder the horizontal axis.

FIG. 6 is a graph showing the results of the rat elevated plus maze testfor the compounds 3, 7, and 10. The vertical axis indicates wall-lessrunning route staying time ratio, and test compounds and doses thereofare shown under the horizontal axis.

MODES FOR CARRYING OUT THE INVENTION

Hereafter, the present invention will be explained in more detail.

(1)

One aspect of the present invention is to provide a pharmaceuticalcomposition comprising a compound represented by the following generalformula (I):

(wherein R represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.

In embodiments of the present invention, the compound represented by thegeneral formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof used inthe pharmaceutical composition according to (1) provided by the presentinvention may be those according to any one of the followings (2) to(58):

(2)

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is C₁₋₁₀ alkyl; cycloalkylalkyl where the cycloalkyl moiety has 3 to6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms; oraralkyl where the aryl moiety has 6 to 10 carbon atoms, and the alkylenemoiety has 1 to 5 carbon atoms.

(3)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (2) mentioned above, wherein R¹ is cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.

(4)

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆ alkyl substituted with 1to 6 halogens; or C₂₋₆ alkyl substituted with C₁₋₆ alkoxy.

(5)

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), whereinR¹ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl,2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl.

(6)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof, whereinaccording to any one of (1) to (5) mentioned above, wherein R² is a 5-to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group; or aheterocyclic ring consisting of the foregoing heterocyclic ring and abenzene ring condensed thereto.

(7)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² is pyridine1-oxide, which may be substituted with 1 to 4 substituents selected fromC₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, and unsubstitutedC₁₋₁₀ alkyl.

(8)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (7) mentioned above, wherein R² is pyridine1-oxide.

(9)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridin-2(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(10)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (9) mentioned above, wherein R² ispyridin-2(1H)-one; 1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆alkyl)pyridin-2(1H)-one.

(11)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridin-4(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(12)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (11) mentioned above, wherein R² ispyridin-4(1H)-one, or 1-(C₁₋₆ alkyl)pyridin-4(1H)-one.

(13)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyridazin-3(2H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(14)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (13) mentioned above, wherein R² ispyridazin-3(2H)-one.

(15)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(16)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrazin-2(1H)-one.

(17)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² is 4H-pyran-4-one,or 2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(18)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (17) mentioned above, wherein R² is4H-pyran-4-one, or 2H-pyran-2-one.

(19)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² isquinolin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(20)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² isquinolin-2(1H)-one.

(21)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6) mentioned above, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

(22)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (6), and (21) mentioned above, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.

(23)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (22) mentioned above, wherein X is CH₂.

(24)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein one of R³ and R⁴ ishydroxy, and the other is hydrogen.

(25)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is halogen; cyano;carbamoyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where theacyl moiety has 2 to 6 carbon atoms, R⁴ is hydrogen or hydroxy, and R⁵is hydrogen.

(26)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is hydroxy;carbamoyl; or C₁₋₆ alkanoyloxy, R⁴ is hydrogen, and RB is hydrogen.

(27)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein R³ is hydroxy, R⁴ ishydrogen, and R⁵ is hydrogen.

(28)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (23) mentioned above, wherein all of R³, R⁴, and R⁵are hydrogens.

(29)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1) to (28) mentioned above, wherein all of R^(6a),R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens.

(30)

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to (1), wherein:

R⁵, R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens,

R¹ is hydrogen; C₁₋₆ alkyl; C₂₋₆ alkenyl; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms,

R² is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatomsselected from N, O and S and at least one carbon atom asring-constituting atoms, containing at least one set of adjacentring-constituting atoms bound by a double bond, and further substitutedwith at least one oxo group, or a heterocyclic ring consisting of theforegoing heterocyclic ring and a benzene ring condensed thereto,

R² binds to Y via a carbon atom of R² as a ring-constituting atom,

R³ and R⁴, which are the same or different, represent hydrogen; hydroxy;halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyloxy;amino; or acylamino where the acyl moiety has 2 to 6 carbon atoms,

X is CH₂, and

Y is C(═O),

provided that the C-s alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; andthe alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the aryl moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thearyl moiety of the C₆₋₁₀ aryloxy as R³ or R⁴ may be substituted with atleast one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, at leastone of the substituents which the aryl moiety of the aralkyl where thearyl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹ may have, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens.

(31)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is C₁₋₆ alkyl; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms.

(32)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof or a solvate thereof accordingto (1), (30), or (31), wherein R¹ is cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.

(33)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆alkyl substituted with 1 to 6 halogens; or C₂₋₆ alkyl substituted withC₁₋₆ alkoxy.

(34)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto (1) or (30), wherein R¹ is allyl, fluoropropyl,2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or2-(aminosulfonyl)ethyl.

(35)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (34), wherein R² is pyridine 1-oxide,pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one,pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one,pyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with a substituent selected from C₁₋₁₀ alkyl substitutedwith 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

(36)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridine 1-oxide,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(37)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (36), wherein R² is pyridine 1-oxide.

(38)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-2(1H)-one,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(39)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-2(1H)-one;1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆ alky)pyridin-2(1H)-one.

(40)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridin-4(1H)-one,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(41)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (40), wherein R² ispyridin-4(1H)-one, or 1-(C₁₋₆ alkyl)pyridin-4(1H)-one.

(42)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyridazin-3(2H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(43)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (42), wherein R² ispyridazin-3(2H)-one.

(44)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyrazin-2(1H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(45)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (44), wherein R² ispyrazin-2(1H)-one.

(46)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is 4H-pyran-4-one, or2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

(47)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (46), wherein R² is 4H-pyran-4-one,or 2H-pyran-2-one.

(48)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is quinolin-2(1H)-one,which may be substituted with 1 to 3 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

(49)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (48), wherein R² isquinolin-2(1H)-one.

(50)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (35), wherein R² is pyrimidin-4(3H)-one,or pyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl.

(51)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), (30) to (35), and (50), wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.

(52)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein one of R³ and R⁴ ishydroxy, and the other is hydrogen.

(53)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is halogen; cyano;carbamoyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where theacyl moiety has 2 to 6 carbon atoms, and R⁴ is hydrogen or hydroxy.

(54)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is hydroxy; carbamoyl;or C₁₋₆ alkanoyloxy, and R⁴ is hydrogen.

(55)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ is hydroxy, and R⁴ ishydrogen.

(56)

The compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto any one of (1), and (30) to (51), wherein R³ and R⁴ are hydrogens.

(57) A compound selected from:

-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2    (1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4    (1H, 3H)-dione,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-1-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one,    and-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,    a tautomer or stereoisomer of the compound, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.    (58) A compound selected from:-   6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one,-   5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione,    and-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,    a tautomer or stereoisomer of the compound, or a pharmaceutically    acceptable salt thereof, or a solvate thereof.

As used herein:

Examples of the C₁₋₆ alkyl include methyl, ethyl, propyl, i-propyl,butyl, t-butyl, pentyl, neopentyl, hexyl, and the like.

Examples of the C₁₋₁₀ alkyl include those exemplified for the C₁₋₆alkyl, as well as heptyl, octyl, and the like.

Examples of the C₁₋₆ alkyl substituted with 1 to 3 halogens include2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl,trifluoromethyl, 3,3,3-trifluoropropyl, and the like.

Examples of the C₂₋₆ alkenyl include 2-propenyl, 3-methyl-2-butenyl, andthe like.

Examples of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms includemethyl, ethyl, and the like substituted with C₃₋₆ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the aralkyl where the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 5 carbon atoms include benzyl group,and phenethyl group.

Examples of the C₃₋₆ cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

Examples of the C₆₋₁₀ aryl include phenyl, naphthyl, and the like.

Examples of the heteroaryl containing 1 to 4 heteroatoms selected fromN, O and S as ring-constituting atoms include pyridyl, furyl,imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl,and the like.

Examples of the heteroarylalkyl where the heteroaryl moiety contains 1to 4 heteroatoms selected from N, O and S as ring-constituting atoms,and the alkylene moiety has 1 to 5 carbon atoms include(pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl,(furan-2-yl)methyl, (furan-3-yl)methyl, (imidazol-2-yl)methyl,(imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl,(thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-2-yl)ethyl,2-(pyridin-3-yl)ethyl, 2-(pyrazol-1-yl)ethyl, 2-(thiophen-2-yl)ethyl,2-(thiophen-3-yl)ethyl, and the like.

Examples of the C₁₋₆ alkanoyl include acetyl, propionyl, and the like.

Examples of the C₁₋₆ alkoxy include methoxy, ethoxy, propoxy, and thelike.

Examples of the C₁₋₆ alkanoyloxy include acetoxy, and the like.

Examples of the alkoxycarbonyl where the alkoxy moiety has 1 to 6 carbonatoms include methoxycarbonyl, ethoxycarbonyl, and the like.

Examples of the halogen include fluorine, chlorine, bromine, iodine, andthe like.

Examples of the C₁₋₆ alkoxy substituted with 1 to 3 halogens includefluoromethoxy, trifluoromethoxy, and the like.

Examples of the C₁₋₆ alkoxy substituted with 1 to 6 halogens includethose mentioned above for the C₁₋₆ alkoxy substituted with 1 to 3halogens, as well as tetrafluoroethoxy, and the like.

Examples of the phenylalkyl where the alkyl has 1 to 3 carbon atomsinclude benzyl, and the like.

Examples of the C₆₋₁₀ aryloxy include phenoxy, and the like.

Examples of the C₁₋₈ alkylamino include methylamino, ethylamino, and thelike.

Examples of the acylamino where the acyl moiety has 2 to 6 carbon atomsinclude acetylamino, and the like.

Examples of the C₆₋₁₀ arylamino include phenylamino, and the like.

Examples of the alkylcarbamoyl where the alkyl moiety has 1 to 6 carbonatoms include ethylcarbamoyl, and the like.

Examples of the dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms include diethylcarbamoyl, and the like.

Examples of the alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms include methylsulfonyl, and the like.

Examples of the alkylsulfinyl where the alkyl moiety has 1 to 6 carbonatoms include methylsulfinyl, and the like.

Examples of the alkylthio where the alkyl moiety has 1 to 6 carbon atomsinclude methylthio, and the like.

Examples of the arylcarbonyl where the aryl moiety has 6 to 10 carbonatoms include benzoyl, and the like.

Examples of the 5- to 7-membered ring that may be formed by combiningR¹¹, R¹² together with the nitrogen atom to which R¹¹ and R¹² bind, andoptionally, 1 or 2 heteroatoms include pyrrolidine, piperidine,morpholine, and the like.

Examples of the heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group as R²include:

(A) pyridine 1-oxide, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridine 1-oxide and2-methylpyridine 1-oxide;

(B) pyridin-2(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridin-2(1H)-one,1-methylpyridin-2(1H)-one, 1-ethylpyridin-2(1H)-one,6-methylpyridin-2(1H)-one, 6-ethylpyridin-2(1H)-one, and6-trifluoromethylpyridin-2(1H)-one;

(C) pyridin-4(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyridin-4(1H)-one,1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one, and1-(fluoroethyl)pyridin-4(1H)-one;

(D) pyridazin-3(2H)-one, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl: for example, pyridazin-3(2H)-oneand 2-methylpyridazin-3(2H)-one;

(E) pyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl: for example, pyrazin-2(1H)-one, and1-methylpyrazin-2(1H)-one;

(F) 4H-pyran-4-one, or 2H-pyran-2-one, which may be substituted with 1to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3fluorine atoms, and unsubstituted C₁₋₁₀ alkyl: for example,4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, and5-methyl-2H-pyran-2-one;

(G) quinolin-2(1H)-one, or quinoline-1-oxide, which may be substitutedwith 1 to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl: for example,quinolin-2(1H)-one, 6-methylquinolin-2(1H)-one, quinoline-1-oxide, and4-methylquinoline-1-oxide;

(H) pyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl:for example, pyrimidin-4(3H)-one, and pyrimidine-2,4(1H,3H)-dione, andthe like.

Examples of tautomer of the compound represented by the aforementionedgeneral formula (I) include tautomers for the aforementionedheterocyclic ring containing 1 to 4 heteroatoms selected from N, O and Sand at least one carbon atom as ring-constituting atoms, containing atleast one set of adjacent ring-constituting atoms bound by a doublebond, and further substituted with at least one oxo group as R², andspecifically, 2-pyridone (lactam) as R² and the corresponding2-hydroxypyridine (lactim) can be mentioned as such an example.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, preferred examples of thepharmaceutically acceptable acid include acid addition salts, andexamples of acid addition salts include salts with an inorganic acid ororganic acid such as hydrochloride, sulfate, fumarate, oxalate,methanesulfonate, and camphorsulfonate.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, examples of thestereoisomer include cis- and trans-isomers, racemates, optically activecompounds, and the like.

As for the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof, the solvate is apharmaceutically acceptable solvate of the compound of the presentinvention or a salt thereof, and includes hydrate.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof may be chemically modifiedinto such a prodrug that it is converted into a pharmacologically activesubstance and exhibits the pharmacological activity (being activated)after it is delivered into the inside of the body or a target site.

Examples of group for constituting such a prodrug include, for example,common protective groups of hydroxy group such as a lower acyl group anda lower alkoxycarbonyl group for the case where the group constituting aprodrug exists on hydroxy group, common protective groups of amino groupsuch as a lower acyl group and a lower alkoxycarbonyl group for the casewhere the group constituting a prodrug exists on nitrogen atom, prodruggroups introduced into a carboxylic acid moiety such aspivaloyloxymethyl (tBu-C(O)O—CH₂—) group, medoxomil group, and cilexetilgroup, and the like.

An atom contained in the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof may bereplaced with a stable isotope such as deuterium.

Hereafter, methods for preparing the compound represented by theaforementioned general formula (I), a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof will be shown below.

The abbreviations used herein are as follows.

ABBREVIATION TABLE

-   Boc: Tert-butoxycarbonyl-   CPM: Cyclopropylmethyl-   DMA: N,N-Dimethylacetamide-   DMAP: N,N-Dimethyl-4-aminopyridine-   DMF: N,N-Dimethylformamide-   DMSO: Dimethyl sulfoxide-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide hexafluorophosphate-   HOAt: 1-Hydroxy-7-azabenzotriazole-   HOBT: 1-Hydroxybenzotriazole-   Me: Methyl-   Ms: Mesyl-   Ph: Phenyl-   TBS: tert-Butyldimethylsilyl-   THF: Tetrahydrofuran-   TLC: Thin layer chromatography-   Ts: Tosyl-   WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

(Preparation Methods)

Compounds Provided by the Present Invention that are CompoundsRepresented by the Aforementioned General Formula (I) Wherein R⁵,R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are Hydrogens

The following compound (I) that is a compound provided by the presentinvention can be obtained by, for example, a deprotection reaction forconverting the following compound (I-A) into the compound (I).

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I) by a deprotection reaction,respectively, or R^(1a) itself may be R¹, R² itself may be R², R^(3a)itself may be R³, and R^(4a) itself may be R⁴. The other symbols havethe same meanings as those defined above.]

In the aforementioned preparation method, the aforementioned compound(I) can be prepared by performing an appropriate known generaldeprotection reaction as required to convert R^(1a) of theaforementioned compound (I-A) into R¹, R^(2a) of the same into R²,R^(3a) of the same into R³, or R^(4a) of the same into R⁴. For example,when R^(1a), R^(2a), R^(3a), or R^(4a) in the aforementioned compound(I-A) contains hydroxy group protected with methyl group, the methylgroup as the protective group can be removed by (1) a method of allowingboron tribromide to act on the aforementioned compound (I-A) indichloromethane, or (2) a method of heating the aforementioned compound(I-A) together with a large excess amount of pyridine hydrochloride inthe absence of solvent, and thereby the aforementioned compound (I) canbe prepared.

When R^(1a), R^(2a), R^(3a), or R^(4a) in the aforementioned compound(I-A) contains hydroxy group protected with tert-butyldimethylsilyl(TBS) group, the TBS group as the protective group can be removed by (3)a method of allowing ammonia dissolved in an appropriate solvent to acton the aforementioned compound (I-A), (4) a method of allowing hydrogenchloride dissolved in an appropriate solvent to act on theaforementioned compound (I-A), or (5) a method of allowingtetrabutylammonium fluoride to act on the aforementioned compound (I-A)in THF, or the like, and thereby the aforementioned compound (I) can beprepared.

When R^(1a), R^(2a), R^(3a), or R^(4a) contains a functional groupprotected with another protective group, the aforementioned compound (I)can be prepared from the aforementioned compound (I-A) under the generaldeprotection conditions such as those explained in Peter G. M. Wuts,“Green's Protective Groups in Organic Synthesis (5th edition, A JohnWiley & Son's, Inc., Publication).

When R^(1a), R^(2a), R^(3a), and R^(4a) have different protectivegroups, and they must be removed under different conditions,deprotection reactions may be successively performed under differentconditions suitable for removing the protective groups as a multi-stepdeprotection reaction to prepare the aforementioned compound (I) fromthe aforementioned compound (I-A).

The aforementioned compound (I-A) can be obtained by, for example,performing a general acylation reaction for the following compound (I-B)mentioned in the reaction formula shown below.

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I) by a deprotection reaction,respectively, or R^(1a) itself may be R¹, R^(2a) itself may be R²,R^(3a) itself may be R³, and R^(4a) itself may be R⁴. L¹ represents aleaving group of a common acylating agent. The other symbols have thesame meanings as those defined above.]

In the aforementioned preparation method, the aforementioned compound(I-A) can be obtained by reacting the aforementioned compound (I-B), acarboxylic acid (R^(2a)COOH), and a condensing agent such as HATU andWSC in the presence of an additive such as HOBT and DMAP, and a basesuch as triethylamine and diisopropylethylamine, as required.

The aforementioned compound (I-A) can also be obtained by reacting theaforementioned compound (I-B), a carboxylic acid chloride (R^(2a)COCl,L¹ in the formula ═Cl) or a carboxylic anhydride (L¹ in theformula=—OC(O)R^(2a)) in the presence of a base such as triethylamine,diisopropylethylamine, and pyridine.

When R^(3a) is hydroxy group (OH), in the acylation reaction mentionedin the above reaction formula, acylation of hydroxy group of R^(3a) alsoprogresses as a side reaction in addition to the desired amidationreaction, and a product corresponding to the aforementioned compound(I-A) wherein R^(3a)=—OC(O)R^(2a) is temporarily obtained as aby-product in the reaction system. However, by treating the reactionsolution with a 2 N ammonia solution in methanol or the like, such acompound is converted again into a compound where R^(3a)=OH in apost-treatment process, and the aforementioned compound (I-A) resultingfrom selective amidation of the secondary amine in the aforementionedcompound (I-B) can be obtained as a result.

In addition, the aforementioned compound (I-A) can also be synthesizedfrom the aforementioned compound (I-B) and a corresponding carboxylicacid (R—COOH) according to the condensation reaction explained inChristian A. G. N. Montalbetti, et al., Tetrahedron, 61(46), 2005,10827-10852.

A desired compound (I-A) can be synthesized by using, for example, thecompounds described in WO2013/035833 such as compound 8 (Example 4,R^(1a)=CPM, X═O, R^(3a)═OMe, R^(4a)═H), compound 33 (Example 29,R^(1a)=Me, X═O, R^(3a) ═OMe, R^(4a)═H), compound 67 (Example 60,R^(1a)=CPM, X═O, R^(3a)═H, R^(4a)═OH), compound 77 (Example 67,R^(1a)=CPM, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 116 (Example 101,R^(1a)=CPM, X═CH₂, R^(3a)═H, R^(4a)═OH), compound 130 (Example 106,R^(1a)=PhCF₂CH₂, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 185 (Example143, R^(1a)=TBSOCH₂CH₂, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 189(Example 144, R^(1a)═(R)—MeCH(OH)CH₂, X═CH₂, R^(3a)═OMe, R^(4a)═H),compound 350 (Example 261, R^(1a)═(S)—MeCH(OH)CH₂, X═CH₂, R^(3a)═OMe,R^(4a)═H), compound 291 (Example 224, R^(1a)=CPM, X═CH₂, R^(3a)═H,R^(4a)═OMe), and compound 297 (Example 228, R^(1a)=CPM, X═CH₂, R^(3a)═H,R^(4a)═H), and the compounds described in WO2014/136305 such as compound29 (Example 27, R^(1a)=BocNHCH₂CH₂, X═CH₂, R^(3a)=OTBS, R^(4a)═H), andcompound 68 (Example 34, R^(1a)=Boc, X═CH₂, R^(3a)═OMe, R^(4a)═H) as theaforementioned compound (I-B), or by a combination of a known conversionof functional group and deprotection reaction performed by a methoddescribed in the aforementioned patent documents.

The following compound (I-A) can also be obtained by, for example, acommon alkylation reaction of the following compound (I-C) mentioned inthe reaction formula shown below.

[In the formulas, R^(1a), R^(2a), R^(3a), and R^(4a) are arbitraryfunctional groups that can be converted into R¹, R², R³, and R⁴ in theaforementioned general formula (I) by a deprotection reaction,respectively, or R^(1a) itself may be R¹, R^(2a) itself may be R²,R^(3a) itself may be R³, and R^(4a) itself may be R⁴. L² represents aleaving group for a common alkylating reaction, R^(1′a) represents sucha substituent that R^(1′a)—CH₂═R^(1a) is satisfied, and the othersymbols have the same meanings as those defined above.]

In the aforementioned preparation method, the aforementioned compound(I-A) can be synthesized by allowing a corresponding aldehyde(R^(1′a)—CHO, R^(1′a) represents such a substituent thatR^(1′a)—CH₂═R^(1a) is satisfied), and a reducing agent such as sodiumtriacetoxyborohydride or sodium cyanoborohydride to act on theaforementioned compound (I-C) in an appropriate solvent in the presenceof an additive such as acetic acid as required.

The aforementioned compound (I-A) can also be synthesized by allowing acorresponding alkylating agent (R^(1a)-L², L² represents an appropriateleaving group, for example, halogen such as Cl, Br, and I, OMs, or OTs)to act on the aforementioned compound (I-C) in a polar solvent such asDMF or an alcohol in the presence of a base such as potassium carbonate.

In addition, the method for introducing the R^(1a) group into theaforementioned compound (I-C) is not limited to the reactions describedabove, and by using a known general alkyl group introduction reactionfor amino group, which may be a multi-step reaction, the aforementionedcompound (I-A) can be prepared from the aforementioned compound (I-C).

The aforementioned compound (I-C) can be synthesized by a combination ofknown functional group conversion and deprotection reaction of anappropriate starting material described in any of the aforementionedreferences according to a method similar to any of the synthesis methodsof, for example, the compounds described in WO2013/035833 such ascompound 11 (Example 7, R^(2a)=Ph, X═O, R^(3a)═OMe, R^(4a) ═H), compound81 (Example 71, R^(2a)=Ph, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound 121(Example 104, R^(2a)=Ph, X═CH₂, R^(3a)=OTBS, R^(4a)═H), compound 149(Example 120, R^(2a)=2-pyridil, X═CH₂, R^(3a)═OMe, R^(4a)═H), compound116 (Example 101, R^(1a)=CPM, X═CH₂, R^(3a)═OMe, R^(4a)═H), and compound217 (Example 163, R^(2a)═CF₃, X═CH₂, R^(3a)=OMe, R^(4a)═H).

The compounds represented by the aforementioned general formula (I) ofthe other types as the compounds provided by the present invention canalso be prepared by a combination of any of the aforementionedpreparation methods, methods described in the examples mentioned later,and those described in Patent documents 4 to 6, Non-patent document 1,and the like.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof shows superior agonistic activity and selectivityfor the opioid δ receptor rather than the opioid and x receptors.Therefore, the compound represented by the aforementioned generalformula (I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof can be used for a pharmaceuticalcomposition that exhibits an opioid δ receptor agonistic activity.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof shows only weak inhibitory action against the hERG(human ether-a-go-go-related gene) potassium channel. Therefore, thecompound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof can be used for a pharmaceutical composition ofwhich risks for retarding the ventricular repolarization and prolongingthe QT interval in humans are low.

Further, the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof shows superior stability againstthe metabolism by human hepatic microsomes. Therefore, the compoundrepresented by the aforementioned general formula (I), a tautomer orstereoisomer thereof, or a pharmaceutically acceptable salt or a solvatethereof can be used for a pharmaceutical composition for oraladministration.

Moreover, the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof intracerebrally acts in animalmodels of depression, anxiety, etc., and shows efficacies thereof.Therefore, they are considered to show good intracerebral migration.

The pharmaceutical composition provided by the present invention isorally or parenterally administered to human or other mammals, andexamples of parenteral administration include intravenousadministration, subcutaneous administration, intramuscularadministration, intraarticular administration, transmucosaladministration, transdermal administration, pernasal administration,rectal administration, and intraspinal administration.

The pharmaceutical composition provided by the present invention may beprepared by mixing the compound represented by the aforementionedgeneral formula (I), a tautomer or stereoisomer thereof, or apharmaceutically acceptable salt or a solvate thereof with apharmaceutically acceptable carrier, for example, an excipient (forexample, lactose, D-mannitol, crystalline cellulose, and glucose),binder (for example, hydroxypropylcellulose (HPC), gelatin, andpolyvinylpyrrolidone (PVP)), lubricant (for example, magnesium stearate,and talc), disintegrating agent (for example, starch, andcarboxymethylcellulose calcium (CMC-Ca)), diluent (for example, waterfor injection, and physiological saline), and if necessary, an additive(for example, pH adjustor, surfactant, solubilizing agent, preservative,emulsifier, isotonic agent, and stabilizer), and may be a pharmaceuticalpreparation in the form of tablet, granule, powder, capsule, suspension,injection, suppository, or the like. For example, when thepharmaceutical composition is prepared as a tablet, it may be preparedby mixing the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof with an excipient, (for example,lactose, D-mannitol, crystalline cellulose, and glucose), disintegratingagent (for example, starch, and carboxymethylcellulose calcium(CMC-Ca)), binder (for example, hydroxypropylcellulose (HPC), gelatin,and polyvinylpyrrolidone (PVP)), lubricant (for example, magnesiumstearate, and talc), and the like. For example, when the pharmaceuticalcomposition is prepared as an injection, it may be prepared by mixingthe compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof with a dispersing agent (for example, surfactantssuch as Tween 80, polysaccharides such as carboxymethylcellulose, sodiumarginine and hyaluronic acid, and polysorbate), preservative (forexample, methylparaben, and propylparaben), isotonic agent (for example,sodium chloride, mannitol, sorbitol, and glucose), pH adjustor (forexample, sodium phosphate, and potassium phosphate), and the like.

The pharmaceutical composition provided by the present invention cancontain the compound represented by the aforementioned general formula(I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof in an amount effective fortherapeutic or prophylactic treatment of an opioid δ receptor-relateddisease (for example, headache).

The dose of the compound represented by the aforementioned generalformula (I), a tautomer or stereoisomer thereof, or a pharmaceuticallyacceptable salt or a solvate thereof may be appropriately determineddepending on type of salt, administration method, symptoms and age ofthe object of administration, and the like. For example, the compoundrepresented by the aforementioned general formula (I), a tautomer orstereoisomer thereof, or a pharmaceutically acceptable salt or a solvatethereof may be administered to a human at a dose of 1 μg to 10 g/day,preferably 0.01 to 2000 mg/day, more preferably 0.1 to 100 mg/day, inthe case of oral administration, or at a dose of 0.1 μg to 1 g/day,preferably 0.001 to 200 mg/day, in the case of intravenousadministration. The daily dose may be administered by 1 to 3 times perday of administration of the whole daily dose or divided portionsthereof.

The compound represented by the aforementioned general formula (I), atautomer or stereoisomer thereof, or a pharmaceutically acceptable saltor a solvate thereof can be used together with another medicament (forexample, an analgesic (for example, non-steroidal anti-inflammatorydrug), and antidepressive and anxiolytic drug (for example, selectiveserotonin reuptake inhibitor)). Such a combinatory use may be attainedby simultaneous administration (for example, administration of mixedagent), or separate successive administrations or administrations withdesired time interval (for example, administrations of separatelyprepared formulations).

As used herein, the opioid δ receptor-related diseases are diseases thatcan be therapeutically or prophylactically treated with an opioid δreceptor agonist, which include, but not limited to, such diseases asmentioned below: depression, anxiety, pain (for example, headache, andfibromuscular pain), glaucoma, urinary incontinence, myocardialischemia, brain ischemia, chronic coughing, hypertension, drugdependence, alcohol dependence, gastritis, prospermia, diarrhea,functional gastrointestinal disturbance, and neurodegenerative diseases(for example, Parkinson's disease, epilepsy, and Alzheimer's disease).

In one embodiment of the present invention, the pharmaceuticalcomposition provided by the present invention can be used fortherapeutic and/or prophylactic treatment of depression or anxiety, andcan be used as a prophylactic and/or therapeutic agent for psychiatricdisorders (antidepressant, anxiolytic drug, etc.), which are included indepressive disorders, anxiety disorders (for example, social anxietydisorder (social phobia), panic disorder, agoraphobia, and generalizedanxiety disorder), bipolar disorders, obsessive-compulsive and relateddisorders, trauma- and stressor-related disorders (for example,posttraumatic stress disorder), and the like described in DSM-5(Diagnostic and Statistical Manual of Mental Disorders, 5th Edition,American Psychiatric Association), or as a prophylactic and/ortherapeutic agent for urinary incontinence, myocardial ischemia, brainischemia, chronic coughing, hypertension, drug dependence, alcoholdependence, gastritis, prospermia, diarrhea, functional gastrointestinaldisturbance, and neurodegenerative diseases (for example, Parkinson'sdisease, epilepsy, and Alzheimer's disease).

In one embodiment of the present invention, the pharmaceuticalcomposition provided by the present invention is a pharmaceuticalcomposition for therapeutic treatment of depression, and is apharmaceutical composition that exhibits rapid efficacy (onset). In oneembodiment of the present invention, the pharmaceutical compositionprovided by the present invention is a pharmaceutical composition fortherapeutic treatment of depression, and is a pharmaceutical compositionthat does not induce tolerance through continuous administration. In oneembodiment of the present invention, the pharmaceutical compositionprovided by the present invention can be used as a prophylactic and/ortherapeutic agent for depression as a symptom associated withAlzheimer's disease.

As described in IOVS, March 2013, Vol. 54, No. 3; J. Neurochem. (2009)108, 741-754; and the like, use of opioid δ receptor agonists forglaucoma has been proposed. Therefore, in one embodiment of the presentinvention, the pharmaceutical composition provided by the presentinvention can be used as a prophylactic and/or therapeutic agent ofglaucoma.

As used herein, depression may be a condition accompanied by a mooddisorder such as depressed feeling, sad feeling, and lonely feeling,activity avolition, delayed thinking, pessimistic idea, and autonomicnerve disorder such as sleep disturbance and anorexia. As used herein,anxiety may be a condition where one feels sense of danger or fearaccompanied by unrest, strain, tachycardia, breathing difficulty, etc.in spite of absence of connection with clearly confirmable stimulus. Thesymptoms or conditions of depression and anxiety include the depressionand anxiety symptoms observed in the psychiatric disorders described inDSM-5 mentioned above (for example, the depression symptoms observed inthe bipolar disorders, and depression and anxiety symptoms observed inPTSD), depression conditions milder than the symptoms of the depressivedisorders described in DSM-5, but persistent to a certain extent, andanxiety conditions milder than the symptoms of the anxiety disordersdescribed in DSM-5, but persistent to a certain extent.

In one embodiment of the present invention, the pharmaceuticalcomposition provided by the present invention is useful for therapeuticand/or prophylactic treatment of all types of pains as an analgesic.

Although there are various classifications of pains, pains are dividedinto acute pains and chronic pains from the aspects of period andproperty thereof. Acute pains are the most important biological signalsfor intensity and range of damages, and examples of acute pain includenociceptive pain caused by an algesic substance released due to tissuedamages, inflammation, etc., and eliminated with healing of the damages.Chronic pains are pains maintained over a period exceeding thereasonable period of time required for usual progress of an acutedisease or wound healing, and examples of chronic pain includeneuropathic pains such as postherpetic pain and pain associated withdiabetic neuropathy, and fibromuscular pain. From the aspect of thecause, pains are divided into nociceptive pains, neuropathic pains, andpsychogenic pains. Examples of the nociceptive pain includeperiarthritis scapulohumeralis, tenosynovitis, rheumatoid arthritis,headache, dentalgia, bruise, incised wound, and the like. Theneuropathic pains are pains caused by nerve damages, and examplesinclude peripheral neuropathic pains such as postherpetic pain, painassociated with diabetic neuropathy, sciatica, and pain associated withperipheral neuropathy caused by intake of an anticancer drug, andcentral neuropathic pains such as postapoplectic pain, post-spinal cordinjury pain, and pain associated with multiple sclerosis. Thepsychogenic pains are pains caused by psychosocial factors such asanxiety and stress caused by social life.

Specific examples of pain and disease accompanied by a pain, of whichthe therapeutic and/or prophylactic treatment the pharmaceuticalcomposition provided by the present invention is useful for, include:phantom limb pain, stump pain, complex regional pain syndrome,polyneuropathy, pain associated with diabetic neuropathy, pain caused byHIV infection, paraneoplastic pain, glossopharyngeal neuralgia,occipital neuralgia, nerve-root damage, nerve plexus damage,postoperative scar syndrome, visceral pain, burn (including sun burn),anginal pain, myelomere or intercostal neuralgia, pain caused bychemotherapy-induced nerve damage, pain associated with rheumatoidarthritis, pain associated with osteoarthritis, headache, migraine,orofacial pain, dentalgia, glossodynia, pain associated withtemporomandibular arthrosis, trigeminal neuralgia, omalgia, painassociated with intervertebral disc herniation, pain associated withcervical spondylosis, pain associated with spinal column stenosis, painassociated with thoracic outlet syndrome, pain associated with brachialplexus traction syndrome, shoulder hand syndrome, pain associated withwhiplash, chest pain, abdominal pain, celialgia, pain associated withcholelithiasis, pain associated with pancreatitis, urolithiasis, painassociated with irritable bowel syndrome, waist back pain, sciatica,pain associated with fracture, pain associated with osteoporosis,arthralgia, pain associated with gout, pain associated with cauda equinasyndrome, pain associated with obliterans ankylosing spondylitis,muscular pain, cramp, myofascial pain syndrome, fibromuscular pain,complex regional pain syndrome, pain associated with arteriosclerosisobliterans, pain associated with Buerger's disease, pain associated withRaynaud's phenomenon, postherpetic pain, causalgia, pain associated withentrapment syndrome, pain associated with carpal tunnel syndrome, painassociated with diabetes, pain associated with Guillain-Barre syndrome,pain associated with Hansen's disease, pain associated withchemotherapy, pain associated with radiotherapy, post-spinal cord injurypain, pain associated with syringomyelia, postapoplectic pain (includingthalamic pain), deafferentation pain, sympathetic nerve-dependent pain,ABC syndrome, multiple sclerosis, pain associated with skin disease,cancerous pain, operative pain, postoperative pain, pain associated withtraumatic injury, pain associated with gangrene, pain associated withsomatoform disorder, pain associated with somatisation disorder, painassociated with depression, pain associated with Parkinson's disease,pain of knee joint, pain associated with arthritis, menstrual pain,intermenstrual pain, labor pain, delivery pain, inflammatory pain,nociceptive pain, psychogenic pain, overactive bladder, cystitis,prostatitis, prostatic pain, and low back pain.

The pharmaceutical composition provided by the present invention ispreferably used for therapeutic and/or prophylactic treatment of painassociated with diabetic peripheral neuropathy, postherpetic pain,post-spinal cord injury pain, postapoplectic pain, pain associated withmultiple sclerosis, pain associated with chronic lumbago, fibromuscularpain, and headache. Headache includes chronic headache and acuteheadache, and headache is preferably migraine, for example, transientmigraine (episodic migraine) or migraine with aura. The pharmaceuticalcomposition provided by the present invention is also useful fortherapeutic treatment of symptoms of depression and/or anxietyassociated with headache.

The pharmaceutical composition provided by the present invention hasantidepressive and/or anxiolytic effect, and accordingly, it is alsouseful for relief of symptoms of depression and/or anxiety associatedwith pain, in addition to the remission and/or amelioration ofaforementioned pain. Therefore, the pharmaceutical composition providedby the present invention may be a pharmaceutical composition fortherapeutic or prophylactic treatment of symptoms of depression and/oranxiety associated with pain.

For example, fibromuscular pain imposes intolerable systemic chronicpain as the core symptom, and is accompanied by affective disorders suchas depression and anxiety as accessory symptoms. In addition to theremission and/or amelioration of fibromuscular pain, the pharmaceuticalcomposition provided by the present invention is also useful forabatement of symptoms of depression and/or anxiety associated with thepain. Therefore, the pharmaceutical composition provided by the presentinvention may be a pharmaceutical composition for therapeutic orprophylactic treatment of symptoms of depression and/or anxietyassociated with fibromuscular pain.

The pharmaceutical composition provided by the present invention is alsouseful for therapeutic or prophylactic treatment of the core symptoms ofParkinson's disease and overactive bladder, and in addition, it is alsoeffective for therapeutic or prophylactic treatment of a pain associatedwith these diseases. Therefore, the pharmaceutical composition providedby the present invention may be a pharmaceutical composition fortherapeutic or prophylactic treatment of a pain associated withParkinson's disease or overactive bladder.

In one embodiment, the present invention provides a method fortherapeutic or prophylactic treatment of any of the diseases mentionedabove, which comprises administering the pharmaceutical compositionprovided by the present invention.

In one embodiment, the present invention provides use of thepharmaceutical composition provided by the present invention fortherapeutic or prophylactic treatment of any of the diseases mentionedabove.

In one embodiment, the present invention provides a method fortherapeutic or prophylactic treatment of any of the diseases mentionedabove, which comprises administering the compound according to any oneof (1) to (58) mentioned above. In one embodiment, the present inventionprovides use of the compound according to any one of (1) to (58)mentioned above for manufacture of a pharmaceutical composition fortherapeutic or prophylactic treatment of any of the diseases mentionedabove.

The present invention also provides the following embodiments 1) to 88):

1)

A method for therapeutic or prophylactic treatment of a pain or adisease accompanied by a pain in a mammalian subject (for example,human) in need thereof, which comprises administering to the subject aneffective amount of a compound represented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.2)

The method according to 1), wherein the pain or the disease accompaniedby a pain is pain associated with diabetic neuropathy, headache,fibromuscular pain, post-spinal cord injury pain, postapoplectic pain(including thalamic pain), multiple sclerosis, postoperative pain, orlow back pain.

3)

The method according to 1) or 2), wherein the pain or the diseaseaccompanied by a pain is headache.

4)

The method according to 3), wherein the headache is migraine.

5)

The method according to 3) or 4), wherein the headache is episodicmigraine or migraine with aura.

6)

The method according to 1) or 2), wherein the pain or the diseaseaccompanied by a pain is fibromuscular pain.

7)

A method for therapeutic or prophylactic treatment of depression oranxiety associated with a pain in a mammalian subject (for example,human) in need thereof, which comprises administering to the subject aneffective amount of a compound represented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; Ca-6 cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy;C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.8)

The method according to 7), wherein the depression or anxiety associatedwith a pain is depression or anxiety associated with headache, ordepression or anxiety associated with fibromuscular pain.

9)

Use of a pharmaceutical composition comprising a compound represented bythe general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₆₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof for use in therapeutic orprophylactic treatment of a pain or a disease accompanied by a pain.10)

The use according to 9), wherein the pain or the disease accompanied bya pain is pain associated with diabetic neuropathy, headache,fibromuscular pain, post-spinal cord injury pain, postapoplectic pain(including thalamic pain), multiple sclerosis, postoperative pain, orlow back pain.

11)

The use according to 9) or 10), wherein the pain or the diseaseaccompanied by a pain is headache.

12)

The use according to 11), wherein the headache is migraine.

13)

The use according to 11) or 12), wherein the headache is episodicmigraine or migraine with aura.

14)

The use according to 9) or 10), wherein the pain or the diseaseaccompanied by a pain is fibromuscular pain.

15)

Use of a pharmaceutical composition comprising a compound represented bythe general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(8a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof for use in therapeutic orprophylactic treatment of depression or anxiety associated with a pain.16)

The use according to 15), wherein the depression or anxiety associatedwith a pain is depression or anxiety associated with headache, ordepression or anxiety associated with fibromuscular pain.

17)

Use of a compound represented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof for manufacture of apharmaceutical composition for therapeutic or prophylactic treatment ofa pain or a disease accompanied by a pain.18)

The use according to 17), wherein the pain or the disease accompanied bya pain is pain associated with diabetic neuropathy, headache,fibromuscular pain, post-spinal cord injury pain, postapoplectic pain(including thalamic pain), multiple sclerosis, postoperative pain, orlow back pain.

19)

The use according to 17) or 18), wherein the pain or the diseaseaccompanied by a pain is headache.

20)

The use according to 19), wherein the headache is migraine.

21)

The use according to 19) or 20), wherein the headache is episodicmigraine or migraine with aura.

22)

The use according to 17) or 18), wherein the pain or the diseaseaccompanied by a pain is fibromuscular pain.

23)

Use of a compound represented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof for manufacture of apharmaceutical composition for therapeutic or prophylactic treatment ofdepression or anxiety associated with a pain.24)

The use according to 23), wherein the depression or anxiety associatedwith a pain is depression or anxiety associated with headache, ordepression or anxiety associated with fibromuscular pain.

25)

A pharmaceutical composition for therapeutic or prophylactic treatmentof a pain or a disease accompanied by a pain, which contains a compoundrepresented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.26)

The pharmaceutical composition according to 25), wherein the pain or thedisease accompanied by a pain is pain associated with diabeticneuropathy, headache, fibromuscular pain, post-spinal cord injury pain,postapoplectic pain (including thalamic pain), multiple sclerosis,postoperative pain, or low back pain.

27)

The pharmaceutical composition according to 25) or 26), wherein the painor the disease accompanied by a pain is headache.

28)

The pharmaceutical composition according to 27), wherein the headache ismigraine.

29)

The pharmaceutical composition according to 27) or 28), wherein theheadache is episodic migraine or migraine with aura.

30)

The pharmaceutical composition according to 25) or 26), wherein the painor the disease accompanied by a pain is fibromuscular pain.

31)

A pharmaceutical composition for therapeutic or prophylactic treatmentof depression or anxiety associated with a pain, which contains acompound represented by the general formula (I):

(wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms,

R² represents heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O and S and at least one carbon atom as ring-constituting atoms,containing at least one set of adjacent ring-constituting atoms bound bya double bond, and further substituted with at least one oxo group,

R² binds to Y via a carbon atom as a ring-constituting atom of R²,

R³, R⁴, and R⁵, which are the same or different, represent hydrogen;hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆alkanoyloxy; nitro; amino; C₁₋₈ alkylamino; C₆₋₁₀ arylamino; oracylamino where the acyl moiety has 2 to 6 carbon atoms,

R^(6a) and R^(6b), which are the same or different, represent hydrogen;fluorine; or hydroxy, or R^(6a) and R^(6b) combine together to represent═O,

R⁷ and R⁸, which are the same or different, represent hydrogen;fluorine; or hydroxy,

R⁹ and R¹⁰, which are the same or different, represent hydrogen; C₁₋₆alkyl; C₆₋₁₀ aryl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or C₂₋₆ alkenyl,

X represents O or CH₂, and

Y represents C(═O),

provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; thealkylene moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thealkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the C₆₋₁₀ aryl as R¹; the aryl moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹; the aryl moiety of the C₆₋₁₀ aryloxy as R³, R⁴, orR⁵; the aryl moiety of the C₆₋₁₀ arylamino as R³, R⁴, or R⁵; the C₆₋₁₀aryl as R⁹ or R¹⁰; the heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms as R⁹ or R¹⁰; the aryl moietyof the aralkyl where the aryl moiety has 6 to 10 carbon atoms, and thealkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroarylmoiety of the heteroarylalkyl where the heteroaryl moiety contains 1 to4 heteroatoms selected from N, O and S as ring-constituting atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may besubstituted with at least one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, thesubstituents that the C₆₋₁₀ aryl as R¹ mentioned above may have,

when R¹ is C₁₋₁₀ alkyl, it may be substituted with NR¹¹R¹², where R¹¹and R¹², which are the same or different, represent hydrogen; C₁₋₁₀alkyl; or aralkyl where the aryl moiety has 6 to 10 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or R¹¹, R¹², the nitrogenatom to which R¹¹ and R¹² bind, and optionally, 1 or 2 heteroatoms maycombine together to form a 5- to 7-membered ring, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens),

a tautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof.32)

The pharmaceutical composition according to 31), wherein the depressionor anxiety associated with a pain is depression or anxiety associatedwith headache, or depression or anxiety associated with fibromuscularpain.

33)

The method, use, or composition according to any one of 1) to 32),wherein, in the general formula (I), R¹ is C₁₋₁₀ alkyl; cycloalkylalkylwhere the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylenemoiety has 1 to 5 carbon atoms; or aralkyl where the aryl moiety has 6to 10 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms.

34)

The method, use, or composition according to any one of 1) to 33),wherein, in the general formula (I), R¹ is cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.

35)

The method, use, or composition according to any one of 1) to 32),wherein, in the general formula (I), R¹ is C₂₋₆ alkyl substituted withhydroxy; C₁₋₆ alkyl substituted with 1 to 6 halogens; or C₂₋₆ alkylsubstituted with C₁₋₆ alkoxy.

36)

The method, use, or composition according to any one of 1) to 32),wherein, in the general formula (I), R¹ is allyl, fluoropropyl,2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or2-(aminosulfonyl)ethyl.

37)

The method, use, or composition according to any one of 1) to 36),wherein, in the general formula (I), R² is a 5- to 7-memberedheterocyclic ring containing 1 to 4 heteroatoms selected from N, O and Sand at least one carbon atom as ring-constituting atoms, containing atleast one set of adjacent ring-constituting atoms bound by a doublebond, and further substituted with at least one oxo group; or aheterocyclic ring consisting of the foregoing heterocyclic ring and abenzene ring condensed thereto.

38)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is pyridine 1-oxide, which maybe substituted with 1 to 4 substituents selected from C₆₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

39)

The method, use, or composition according to any one of any one of 1) to38), wherein, in the general formula (I), R² is pyridine 1-oxide.

40)

The method, use, or composition according to any one of any one of 1) to37), wherein, in the general formula (I), R² is pyridin-2(1H)-one, whichmay be substituted with 1 to 4 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

41)

The method, use, or composition according to any one of 1) to 37), and40), wherein, in the general formula (I), R² is pyridin-2(1H)-one;1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆ alkyl)pyridin-2(1H)-one.

42)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is pyridin-4(1H)-one, which maybe substituted with 1 to 4 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

43)

The method, use, or composition according to any one of 1) to 37), and42), wherein, in the general formula (I), R² is pyridin-4(1H)-one, or1-(C₁₋₆ alkyl)pyridin-4(1H)-one.

44)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is pyridazin-3(2H)-one, whichmay be substituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

45)

The method, use, or composition according to any one of 1) to 37), and44), wherein, in the general formula (I), R² is pyridazin-3(2H)-one.

46)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is pyrazin-2(1H)-one, which maybe substituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

47)

The method, use, or composition according to any one of 1) to 37), and46), wherein, in the general formula (I), R² is pyrazin-2(1H)-one.

48)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is 4H-pyran-4-one, or2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

49)

The method, use, or composition according to any one of 1) to 37), and48), wherein, in the general formula (I), R² is 4H-pyran-4-one, or2H-pyran-2-one.

50)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is quinolin-2(1H)-one, which maybe substituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

51)

The method, use, or composition according to any one of 1) to 37), and50), wherein, in the general formula (I), R² is quinolin-2(1H)-one.

52)

The method, use, or composition according to any one of 1) to 37),wherein, in the general formula (I), R² is pyrimidin-4(3H)-one, orpyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl.

53)

The method, use, or composition according to any one of 1) to 37), and52), wherein, in the general formula (I), R² is pyrimidin-4(3H)-one, orpyrimidine-2,4(1H,3H)-dione.

54)

The method, use, or composition according to any one of 1) to 53),wherein, in the general formula (I), X is CH₂.

55)

The method, use, or composition according to any one of 1) to 54),wherein, in the general formula (I), one of R³ and R⁴ is hydroxy, andthe other is hydrogen.

56)

The method, use, or composition according to any one of 1) to 54),wherein, in the general formula (I), R³ is halogen; cyano; carbamoyl;C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where the acyl moietyhas 2 to 6 carbon atoms, R⁴ is hydrogen or hydroxy, and R⁵ is hydrogen.

57)

The method, use, or composition according to any one of 1) to 54),wherein, in the general formula (I), R³ is hydroxy; carbamoyl; or C₁₋₆alkanoyloxy, R⁴ is hydrogen, and R⁵ is hydrogen.

58)

The method, use, or composition according to any one of 1) to 54),wherein, in the general formula (I), R³ is hydroxy, R⁴ is hydrogen, andR⁵ is hydrogen.

59)

The method, use, or composition according to any one of 1) to 54),wherein, in the general formula (I), all of R³, R⁴, and R⁵ arehydrogens.

60)

The method, use, or composition according to any one of 1) to 59),wherein, in the general formula (I), all of R⁶, R^(6b), R⁷, R⁸, R⁹, andR¹⁰ are hydrogens.

61)

The method, use, or composition according to any one of 1) to 32),wherein:

R⁵, R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens,

R¹ is hydrogen; C₁₋₆ alkyl; C₂₋₆ alkenyl; cycloalkylalkyl where thecycloalkyl moiety has 3 to 6 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms; or aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms,

R² is a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatomsselected from N, O and S and at least one carbon atom asring-constituting atoms, containing at least one set of adjacentring-constituting atoms bound by a double bond, and further substitutedwith at least one oxo group, or a heterocyclic ring consisting of theforegoing heterocyclic ring and a benzene ring condensed thereto,

R² binds to Y via a carbon atom of R² as a ring-constituting atom,

R³ and R⁴, which are the same or different, represent hydrogen; hydroxy;halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyloxy;amino; or acylamino where the acyl moiety has 2 to 6 carbon atoms,

X is CH₂, and

Y is C(═O),

provided that the C₁₋₆ alkyl as R¹; the alkylene moiety and cycloalkylmoiety of the cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; andthe alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from

1 to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl;C₁₋₆ alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has1 to 6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms,

the aryl moiety of the aralkyl where the aryl moiety has 6 to 10 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; and thearyl moiety of the C₆₋₁₀ aryloxy as R³ or R⁴ may be substituted with atleast one substituent selected from

C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy,

the heterocyclic ring as R² may have, besides the oxo group, at leastone of the substituents which the aryl moiety of the aralkyl where thearyl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹ may have, and

the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹ maybe substituted with at least one substituent selected from phenyl, andC₁₋₆ alkyl substituted with 1 to 3 halogens.

62)

The method, use, or composition according to any one of 1) to 32), and61), wherein, in the general formula (I), R¹ is C₁₋₆ alkyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; or aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms.

63)

The method, use, or composition according to any one of 1) to 32), 61),and 62), wherein, in the general formula (I), R¹ is cycloalkylalkylwhere the cycloalkyl moiety has 3 to 6 carbon atoms, and the alkylenemoiety has 1 to 5 carbon atoms.

64)

The method, use, or composition according to any one of 1) to 32), and61), wherein, in the general formula (I), R¹ is C₂₋₆ alkyl substitutedwith hydroxy; C₁₋₆ alkyl substituted with 1 to 6 halogens; or C₂₋₆ alkylsubstituted with C₁₋₆ alkoxy.

65)

The method, use, or composition according to any one of 1) to 32), and61), wherein, in the general formula (I), R¹ is allyl, fluoropropyl,2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or2-(aminosulfonyl)ethyl.

66)

The method, use, or composition according to any one of 1) to 32), and61) to 65), wherein, in the general formula (I), R² is pyridine 1-oxide,pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one,pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one,pyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with a substituent selected from C₁₋₁₀ alkyl substitutedwith 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

67)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² is pyridine 1-oxide,which may be substituted with 1 to 4 substituents selected from C₁₋₁₀alkyl substituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀alkyl.

68)

The method, use, or composition according to any one of any one of 1) to32), and 61) to 67), wherein, in the general formula (I), R² is pyridine1-oxide.

69)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyridin-2(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

70)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyridin-2(1H)-one; 1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or6-(C₁₋₆-alky)pyridin-2(1H)-one.

71)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyridin-4(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

72)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyridin-4(1H)-one, or 1-(C₁₋₆ alkyl)pyridin-4(1H)-one.

73)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyridazin-3(2H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

74)

The method, use, or composition according to any one of 1) to 32), 61)to 66), and 73), wherein, in the general formula (I), R² ispyridazin-3(2H)-one.

75)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

76)

The method, use, or composition according to any one of 1) to 32), 61)to 66), and 75), wherein, in the general formula (I), R² ispyrazin-2(1H)-one.

77)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² is 4H-pyran-4-one,or 2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

78)

The method, use, or composition according to any one of 1) to 32), 61)to 66), and 77), wherein, in the general formula (I), R² is4H-pyran-4-one, or 2H-pyran-2-one.

79)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² isquinolin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.

80)

The method, use, or composition according to any one of 1) to 32), 61)to 66), and 79), wherein, in the general formula (I), R² isquinolin-2(1H)-one.

81)

The method, use, or composition according to any one of 1) to 32), and61) to 66), wherein, in the general formula (I), R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.

82)

The method, use, or composition according to any one of 1) to 32), 61)to 66), and 81), wherein, in the general formula (I), R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.

83)

The method, use, or composition according to any one of 1) to 32), and61) to 82), wherein, in the general formula (I), one of R³ and R⁴ ishydroxy, and the other is hydrogen.

84)

The method, use, or composition according to any one of 1) to 32), and61) to 82), wherein, in the general formula (I), R³ is halogen; cyano;carbamoyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where theacyl moiety has 2 to 6 carbon atoms, and R⁴ is hydrogen or hydroxy.

85)

The method, use, or composition according to any one of 1) to 32), and61) to 82), wherein, in the general formula (I), R³ is hydroxy;carbamoyl; or C₁₋₆ alkanoyloxy, and R⁴ is hydrogen.

86)

The method, use, or composition according to any one of 1) to 32), and61) to 82), wherein, in the general formula (I), R³ is hydroxy, and R⁴is hydrogen.

87)

The method, use, or composition according to any one of 1) to 32), and61) to 82), wherein, in the general formula (I), R³ and R⁴ arehydrogens.

88)

The method, use, or composition according to any one of 1) to 32),wherein the compound represented by the general formula (I) is acompound selected from:

-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   4-((1S,3aR,5aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   3-((1S,3aR,5aS,6R,11bR,11S)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-1-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin    1-oxide,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiniinoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyO-1-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   5-((1 S,    3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,-   3-((1S,3aR,5aS,6R,11bR,11cS)    14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one,-   4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine    1-oxide,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,-   3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,-   6-((1S,3aR,5aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,-   6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one,    and-   5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one.

Hereafter, the present invention will be further explained in moredetail with reference to reference examples and examples. However, thepresent invention is not limited to these examples.

Names of the compounds mentioned in the examples and reference examplesare obtained by converting structural formulas depicted with ChemDrawver. 14, Cambridge Software into English compound names with a namingalgorithm of the same software, and translating them into Japanesenames.

The NMR data and the measured values of mass spectrometry (ESI+ or ESI−)of Examples 1 to 34 are shown in Tables 1 to 5.

EXAMPLES Reference Example 1-1 Synthesis of(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol

To a 300-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole(372 mg, 1.02 mmol) synthesized according to the method ofWO2013/035833, Example 67 was added, and dissolved in dichloromethane (5mL), the solution was vigorously stirred at 0° C. for 20 minutes, then a1.0 M solution of boron tribromide in dichloromethane (5 mL, 5 mmol) wasadded to the solution, and the resulting mixture was stirred at roomtemperature for 30 minutes. To the reaction solution, methanol (10 mL)was added at 0° C., and the resulting mixture was stirred at the sametemperature for 1 hour.

The reaction solution was concentrated under reduced pressure, and theresidue was suspended in chloroform (50 mL), and washed with 6% aqueousammonia (20 mL). The aqueous layer was extracted twice with chloroform(30 mL), the combined organic layers were dried over anhydrous sodiumsulfate, the insoluble matter was separated by filtration, and then thefiltrate was concentrated under reduced pressure to obtain the titlecompound (356 mg, 100%) as brown foam.

[Alternative Method]

To a 500-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole(3.58 g, 9.82 mmol) synthesized according to the method ofWO2013/035833, Example 67, and pyridine hydrochloride (87 g, 753 mmol)were added, and the mixture was stirred at 200° C. for 1 hour. After thereaction, the reaction mixture was returned to room temperature,saturated aqueous potassium carbonate was added to the produced solid todissolve it, the solution was extracted with ethyl acetate andchloroform, and the combined organic layers were dried over anhydroussodium sulfate. The insoluble matter was separated by filtration, andthen the filtrate was concentrated under reduced pressure to obtain thetitle compound (3.30 g, 96%) as brown foam.

¹H NMR (CDCl₃, 400 MHz): δ 6.94 (d, 1H, J=8.2 Hz), 6.70 (dd, 1H, J=8.2,2.8 Hz), 6.50 (d, 1H, J=2.3 Hz), 3.73-3.76 (m, 1H), 3.23-3.31 (m, 2H),3.05-3.12 (m, 2H), 2.77-2.99 (m, 4H), 2.55 (dd, 1H, J=11.0, 5.0 Hz),2.31 (d, 1H, J=6.4 Hz), 1.91-2.11 (m, 2H), 1.69-1.74 (m, 1H), 1.20-1.45(m, 3H), 0.93-1.10 (m, 3H), 0.77-0.83 (m, 1H), 0.42-0.51 (m, 2H),0.05-0.14 (m, 2H)

Reference Example 1-2 Synthesis of(1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole

To a 200-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(694 mg, 1.98 mmol) synthesized according to the method of ReferenceExample 1-1 was added, and dissolved in DMF (20 mL), imidazole (241 mg,3.54 mmol) and tert-butyldimethylchlorosilane (498 mg, 3.31 mmol) wereadded to the solution at room temperature, and the resulting mixture wasstirred at room temperature for 2 hours. Since it was confirmed that thestarting material remained in the reaction solution, imidazole (529 mg,7.77 mmol) and tert-butyldimethylchlorosilane (503 mg, 3.34 mmol) wereadded to the reaction solution, and the resulting mixture was stirred atroom temperature for 18 hours. To the reaction solution, water (150 mL)was added, and the resulting mixture was extracted with a mixed solventof ethyl acetate and hexane (1:1, 100 mL). 6% Aqueous ammonia (30 mL)was added to the aqueous layer to make it basic, and then the resultingmixture was extracted twice with a mixed solvent of ethyl acetate andhexane (1:1, 100 mL). The combined organic layers were dried overanhydrous magnesium sulfate, then the insoluble matter was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (silica gel, 25 g)using methanol/chloroform (concentration gradient, 0 to 50%) and thenmethanol containing 10% concentrated aqueous ammonia/chloroform(concentration gradient, 20 to 50%) as the elution solvent to obtain thetitle compound (456 mg, 50%) as yellow syrup, and obtain the startingmaterial,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(265 mg, 38%).

¹H NMR (CDCl₃, 400 MHz): δ 6.94 (d, 1H, J=8.2 Hz), 6.65 (d, 1H, J=2.8Hz), 6.59 (dd, 1H, J=8.2, 2.8 Hz), 3.49-3.53 (m, 1H), 3.33 (dd, 1H,J=8.2, 7.8 Hz), 3.08-3.18 (m, 2H), 2.77-2.96 (m, 4H), 2.71 (t, 1H, J=7.3Hz), 2.51-2.55 (m, 1H), 2.30 (d, 2H, J=6.4 Hz), 1.90-2.03 (m, 2H),1.63-1.68 (m, 1H), 1.35-1.43 (m, 1H), 0.91-1.13 (m, 14H), 0.77-0.83 (m,1H), 0.42-0.51 (m, 2H), 0.16 (s, 6H), 0.08-0.10 (m, 2H)

Example 1 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide

To a 50-mL round bottom flask,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(31 mg, 87 μmol) synthesized in Reference Example 1, 2-carboxypyridine1-oxide (32 mg, 0.23 mmol), and HATU (125 mg, 0.33 mmol) were added, andsuspended in THF (1.5 mL), then triethylamine (70 μL, 0.50 mmol) and DMA(200 μL) were added to the suspension, and the resulting mixture wasstirred for 1 hour at room temperature. To the reaction mixture, a 2 Nsolution of ammonia in methanol (2 mL) was added, and the resultingmixture was stirred at the same temperature for 1 hour. The reactionsolution was concentrated under reduced pressure, the obtained residuewas suspended in 6% aqueous ammonia, and the suspension was extractedwith ethyl acetate. The combined organic layers were washed withsaturated brine, and then dried over anhydrous magnesium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to column chromatography (aminosilica gel, 16 g) usingmethanol and chloroform (concentration gradient, 0 to 50%) as theelution solvent to obtain the title compound (18 mg, 44%) as whitesolid.

Example 2 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(36 mg, 0.10 mmol), 4-carboxypyridine 1-oxide (42 mg, 0.30 mmol),triethylamine (70 μL, 0.50 mmol), and HATU (108 mg, 0.28 mmol) werereacted. The reaction solution was directly subjected to columnchromatography (silica gel, 10 g) using methanol and ethyl acetatecontaining 5% triethylamine (concentration gradient, 10 to 50%) as theelution solvent, and thereby purified. The obtained syrup was dissolvedin methanol, then powdered by adding chloroform and tert-butyl methylether to the solution, and then collected by filtration to obtain thetitle compound (30 mg, 62%) as weakly brown solid.

Example 3 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(39 mg, 0.11 mmol), 2-oxo-1,2-dihydropyridine-3-carboxylic acid (39 mg,0.28 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (130 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was concentrated under reduced pressure, and the residue wasdirectly subjected to column chromatography (silica gel, 10 g) usingmethanol and ethyl acetate containing 5% triethylamine (concentrationgradient, 10 to 50%) as the elution solvent, and thereby purified. Theobtained residue was powdered from 6% aqueous ammonia to obtain thetitle compound (13 mg, 25%) as pale yellow powder.

Example 4 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(34 mg, 97 μmol), 3-carboxypyridine 1-oxide (40 mg, 0.29 mmol),triethylamine (70 μL, 0.50 mmol), and HATU (125 mg, 0.33 mmol) werereacted. To the reaction solution, a 2 N solution of ammonia in methanolwas added to terminate the reaction, then the reaction solution wasconcentrated under reduced pressure, and the residue was directlysubjected to column chromatography (silica gel, 25 g) using a 0.1 Nsolution of ammonia in methanol and chloroform (concentration gradient,0 to 50%) as the elution solvent, and thereby purified. The obtainedsyrup was dissolved in methanol, then powdered by adding tert-butylmethyl ether to the solution, and then collected by filtration to obtainthe title compound (14 mg, 31%) as weakly brown amorphous substance.

Example 5 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(34 mg, 96 μmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (40 mg,0.29 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (132 mg, 0.35mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wasdirectly subjected to column chromatography (silica gel, 10 g) using a0.1 N solution of ammonia in methanol and chloroform (concentrationgradient, 1 to 50%) as the elution solvent, and thereby purified. Inorder to eliminate impurities, the obtained compound was suspended inchloroform, and then the suspension was washed with 6% aqueous ammonia.The aqueous layer was extracted with chloroform, then the combinedorganic layers were dried over anhydrous sodium sulfate, then theinsoluble substance was separated by filtration, and the filtrate wasconcentrated under reduced pressure to obtain the title compound (14 mg,30%) as pale yellow powder.

Reference Example 2 Synthesis of1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

This compound was synthesized by a method similar to the methoddescribed in WO2006/107254.

To a 50-mL round bottom flask, 2-oxo-1,2-dihydropyridine-3-carboxylicacid (500 mg, 3.59 mmol) was added, and suspended in methanol (5 mL) andwater (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was addedto the suspension, and the resulting mixture was stirred at 100° C. for15 minutes. The reaction solution was returned to room temperature,iodomethane (2.6 mL, 41.8 mmol) was added to the reaction solution, andthe resulting mixture was stirred at 100° C. for 45 minutes, and thenconcentrated under reduced pressure until the solvent volume was reducedby half. To the reaction solution, 3 N hydrochloric acid (20 mL) wasadded, and the produced solid was collected by filtration, washed withwater and acetonitrile, and then dried under reduced pressure to obtainthe title compound (64.9 mg, 12%) as white powder.

¹H NMR (CD₃OD, 400 MHz): δ 8.43 (dd, 1H, J=6.9, 2.3 Hz), 8.05 (dd, 1H,J=6.9, 2.3 Hz), 6.65 (t, 1H, J=6.9 Hz), 3.70 (s, 3H)

Example 6 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(30 mg, 86 mol), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid(29 mg, 0.19 mmol) synthesized in Reference Example 2,diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was suspended in saturated aqueoussodium hydrogen carbonate, then the suspension was extracted withchloroform, and the organic layer was dried over anhydrous sodiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using a 1.4 N solution ofammonia in methanol and chloroform (concentration, 5%) as the developingsolvent to obtain the title compound (26.2 mg, 63%) as pale yellowamorphous substance.

Example 7 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(66 mg, 0.19 mmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (83 mg,0.59 mmol), triethylamine (150 μL, 1.10 mmol), and HATU (262 mg, 0.69mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wasdirectly subjected to column chromatography (aminosilica gel, 10 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent, and thereby purified. The obtained syrup was dissolvedin methanol, and powdered by adding tert-butyl methyl ether to thesolution to obtain the title compound (83 mg, 94%) as brown solid.

Example 8 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 mol), 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid(19 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU(48 mg, 0.13 mmol) were reacted in the same manner as that of Example 1,except that DMF was used as the solvent instead of THF and DMA. To thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was subjected to preparative TLCusing a 1.4 N solution of ammonia in methanol and chloroform(concentration, 10%) as the developing solvent, and thereby purified.Then, in order to eliminate impurities, the obtained solid was furthersuspended in saturated aqueous potassium carbonate, and then extractedwith chloroform. The organic layer was dried over anhydrous sodiumsulfate, then the inorganic matter was separated by filtration, and thefiltrate was concentrated under reduced pressure to obtain the titlecompound. The obtained compound was given as a hydrochloride saltaccording to Example 32 for use in the biological activity test.

Example 9 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid(29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU(72 mg, 0.19 mmol) were reacted in the same manner as that of Example 1,except that dichloromethane was used as the solvent instead of THF andDMA. To the reaction solution, a 1.4 N solution of ammonia in methanolwas added to terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended insaturated aqueous sodium hydrogen carbonate, and then the suspension wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate, the insoluble substance was separated by filtration, andthen the filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using methanol and chloroform(concentration, 10%) as the developing solvent to obtain the titlecompound (31.1 mg, 75%) as white amorphous substance.

Reference Example 3 Synthesis of1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

To a 50-mL round bottom flask, 6-oxo-1,6-dihydropyridine-2-carboxylicacid (500 mg, 3.59 mmol) was added, and suspended in methanol (5 mL) andwater (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was addedto the suspension, and the resulting mixture was stirred at 100° C. for15 minutes. The reaction solution was returned to room temperature,iodomethane (2.6 mL, 41.8 mmol) was added to the reaction solution, andthe resulting mixture was stirred at 100° C. for 1 hour, and thenconcentrated under reduced pressure until the solvent volume was reducedby half. To the reaction solution, 3 N hydrochloric acid was added, andthe produced solid was collected by filtration, washed with water andacetonitrile, and then dried under reduced pressure to obtain the titlecompound (339 mg, 62%) as white powder. ¹H NMR (DMSO-de, 400 MHz): δ7.45 (dd, 1H, J=9.2, 6.9 Hz), 6.72 (dd, 1H, J=6.9, 1.4 Hz), 6.59 (dd,1H, J=9.2, 1.4 Hz), 3.51 (s, 3H)

Example 10 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(30 mg, 86 mol), 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid(29 mg, 0.19 mmol) synthesized according to the method of ReferenceExample 3, diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg,0.19 mmol) were reacted in the same manner as that of Example 1, exceptthat dichloromethane was used as the solvent instead of THF and DMA. Tothe reaction solution, a 1.4 N solution of ammonia in methanol was addedto terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended insaturated aqueous sodium hydrogen carbonate, and then the suspension wasextracted with chloroform. The organic layer was dried over anhydroussodium sulfate, the insoluble substance was separated by filtration, andthen the filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to preparative TLC using methanol and chloroform(concentration, 10%) as the developing solvent to obtain the titlecompound (32.7 mg, 79%) as white amorphous substance.

Example 11 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,111cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(54 mg, 0.15 mmol), 2-methoxyisonicotinic acid (54 mg, 0.35 mmol),triethylamine (140 μL, 1.00 mmol), and HATU (195 mg, 0.51 mmol) werereacted. To the reaction solution, a 2 N solution of ammonia in methanolwas added to terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended inchloroform, and then the suspension was washed with 6% aqueous ammonia.The aqueous layer was extracted with chloroform, the combined organiclayers were dried over anhydrous magnesium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The obtained residue was subjected to columnchromatography (aminosilica gel, 16 g) using methanol containing 10%concentrated aqueous ammonia and chloroform as the elution solvent toobtain((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanone(61 mg, 82%) as white solid.

¹H NMR (DMSO-d₆, 400 MHz): δ 8.20 (d, 0.6H, J=6.0 Hz), 8.15 (d, 0.4H,J=5.0 Hz), 6.88-6.97 (m, 2H), 6.80 (s, 0.6H), 6.74 (s, 0.4H), 6.64 (d,0.6H, J=2.8 Hz), 6.56 (dd, 0.6H, J=8.2, 2.3 Hz), 6.45-6.51 (m, 0.8H),4.06-4.16 (m, 1H), 3.92 (s, 1.8H), 3.88 (s, 1.2H), 3.64-3.69 (m, 0.6H),3.43-3.37 (m, 2H), 3.14-3.17 (m, 1H), 2.97-3.09 (m, 1H), 2.82-2.91 (m,2H), 2.52-2.56 (m, 1H), 2.29-2.31 (m, 2H), 1.88-2.08 (m, 2H), 1.66-1.80(m, 1H), 1.42-1.57 (m, 1.6H), 1.02-1.23 (m, 2.4H), 0.75-0.96 (m, 2H),0.42-0.49 (m, 2H), 0.05-0.14 (m, 2H)

To a 100-mL round bottom flask,((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanoneobtained above (48 mg, 98 gmol), and pyridine hydrochloride (2.88 g, 25mmol) were added, and the resulting mixture was stirred at 200° C. for10 minutes with heating. The reaction solution was cooled to roomtemperature, and then suspended in 6% aqueous ammonia, and thesuspension was extracted with ethyl acetate. The combined organic layerswere dried over anhydrous magnesium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The residue was subjected to columnchromatography (aminosilica gel, 8 g) using methanol and chloroform(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (35 mg, 75%) as white solid.

Example 12 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(32 mg, 90 μmol), 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylicacid monohydrate (35 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol),and HATU (114 mg, 0.30 mmol) were reacted. To the reaction solution, a 2N solution of ammonia in methanol was added to terminate the reaction,and then the reaction solution was concentrated under reduced pressure.The obtained residue was suspended in saturated aqueous sodium hydrogencarbonate, and the suspension was extracted three times with a 5:1 mixedsolution of chloroform and methanol. The combined organic layers weredried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to preparative TLCusing methanol containing 10% concentrated aqueous ammonia andchloroform (concentration, 25%) as the developing solvent to obtain thetitle compound (16 mg, 35%) as white solid.

Example 13 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-3-carboxylic acid (28 mg,0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was suspended in saturated aqueous sodium hydrogen carbonate,and the suspension was extracted three times with ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol containing 10% concentratedaqueous ammonia and chloroform (concentration, 15%) as the developingsolvent to obtain the title compound (19 mg, 44%) as white solid.

Example 14 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-2-carboxylic acid (28 mg,0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, then the reactionsolution was suspended in saturated aqueous sodium hydrogen carbonate,and the suspension was extracted three times with a 5:1 mixed solutionof chloroform and methanol. The combined organic layers were dried overanhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to preparative TLC usingmethanol containing 10% concentrated aqueous ammonia and chloroform(concentration, 15%) as the developing solvent to obtain the titlecompound (8 mg, 20%) as white solid.

Example 15 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(32 mg, 90 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid(31 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg,0.30 mmol) were reacted. To the reaction solution, a 2 N solution ofammonia in methanol was added to terminate the reaction, then thereaction solution was suspended in saturated aqueous sodium hydrogencarbonate, and the suspension was extracted three times with chloroform.The combined organic layers were dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to preparative TLC using methanol and chloroform(concentration, 5%) as the developing solvent to obtain the titlecompound (41 mg, 94%) as white solid.

Example 16 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(30 mg, 85.9 μmol), 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (31mg, 0.22 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (129 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in 6% aqueous ammonia, then the suspension was extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to column chromatography (aminosilica gel, 16 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent to obtain the title compound (27 mg, 66%) as whitesolid.

Example 17 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(33 mg, 95 μmol), 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (50 mg,0.26 mmol), triethylamine (70 IpL, 0.50 mmol), and HATU (128 mg, 0.34mmol) were reacted. To the reaction solution, a 2 N solution of ammoniain methanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in 6% aqueous ammonia, then the suspension was extracted withethyl acetate, and the organic layer was dried over anhydrous magnesiumsulfate. The insoluble substance was separated by filtration, and thenthe filtrate was concentrated under reduced pressure. The obtainedresidue was subjected to column chromatography (aminosilica gel, 16 g)using methanol and chloroform (concentration gradient, 0 to 30%) as theelution solvent to obtain the title compound (28 mg, 56%) as whitesolid.

Example 18 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-2H-pyran-2-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 μmol), 2-oxo-2H-pyran-5-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. One hourafter the start of the reaction, 1 N hydrochloric acid was added to thereaction solution, and the resulting mixture was further stirred. To thereaction solution, aqueous potassium carbonate was added to terminatethe reaction, and then the reaction solution was extracted withchloroform. The organic layer was dried over sodium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol and chloroform(concentration, 5%) as the developing solvent to obtain the titlecompound (4.0 mg, 15%) as brown amorphous substance.

Example 19 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-4H-pyran-4-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 mol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 2 N solution of methylamine in methanol (0.3 mL,0.6 mmol) was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in saturated aqueous sodium hydrogen carbonate, and then thesuspension was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to preparative TLC usingmethanol and chloroform (concentration, 10%) as the developing solventto obtain the title compound (4.4 mg, 16%) as brown amorphous substance.

Example 20 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol),diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol)were reacted in the same manner as that of Example 1, except thatdichloromethane was used as the solvent instead of THF and DMA. To thereaction solution, a 2 N solution of methylamine in methanol (3.0 mL,6.0 mmol) was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The residue wassuspended in saturated aqueous potassium carbonate, and then thesuspension was extracted with chloroform. The organic layer was driedover anhydrous sodium sulfate, the insoluble substance was separated byfiltration, and then the filtrate was concentrated under reducedpressure. The obtained residue was subjected to column chromatography(aminosilica gel, 8 g) using methanol and chloroform (concentrationgradient, 0 to 10%) as the elution solvent to obtain the title compound(19 mg, 68%) as weakly brown amorphous substance.

Example 21 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 μmol), 5-oxo-4,5-dihydropyrazine-2-carboxylic acid (18 mg,0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg,0.13 mmol) were reacted in the same manner as that of Example 1, exceptthat dichloromethane was used as the solvent instead of THF and DMA. Tothe reaction solution, a 1.4 N solution of ammonia in methanol was addedto terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended inaqueous potassium carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland chloroform (concentration gradient, 5 to 30%) as the elution solventto obtain the title compound (12.2 mg, 45%) as weakly brown amorphoussubstance.

Example 22 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide

To a 10-mL test tube,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide (52 mg, 0.11 mmol) synthesized in Example 1 was added, andsuspended in THF (1 mL), then triethylamine (45 μL, 0.32 mmol) andacetyl chloride (15 μL, 0.21 mmol) were added to the suspension, and theresulting mixture was stirred at room temperature for 1 hour. Since itwas confirmed that the starting material remained in the reactionsolution, triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL,0.21 mmol) were added again, and the resulting mixture was stirred atroom temperature for 1 hour. To the reaction solution, saturated aqueoussodium hydrogen carbonate and ethyl acetate were added, the resultingmixture was vigorously stirred for 20 minutes, and then the aqueouslayer was separated, and extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous magnesium sulfate, then theinsoluble substance was separated by filtration, and the filtrate wasconcentrated under reduced pressure to obtain the title compound (51 mg,89%) as yellow amorphous substance.

Example 23 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole(27 mg, 79 μmol) prepared according the method described inWO2013/035833 for the compound 297 (Example 228),6-oxo-1,6-dihydropyridine-2-carboxylic acid (18 mg, 0.16 mmol),triethylamine (50 μL, 0.36 mmol), and HATU (70 mg, 0.18 mmol) werereacted. To the reaction solution, a 2 N solution of ammonia in methanolwas added to terminate the reaction, and then the reaction solution wasconcentrated under reduced pressure. The residue was suspended in 6%aqueous ammonia, then the suspension was extracted with ethyl acetate,and the organic layer was dried over anhydrous magnesium sulfate. Theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to column chromatography (aminosilica gel, 8 g) using methanoland chloroform (concentration gradient, 0 to 20%) as the elutionsolvent. The obtained compound was dissolved in methanol, and powderedby adding tert-butyl methyl ether to the solution to obtain the titlecompound (24 mg, 67%) as white solid.

Reference Example 4 Synthesis of 3-oxo-3,4-dihydropyrazine-2-carboxylicacid

This compound was synthesized by the method described in WO2009/033084,and ¹H NMR spectrum thereof coincided to the data described in Syn.Commun., 2010, 40(20). 2988-2999.

To a 50-mL round bottom flask, 3-aminopyrazine-2-carboxylic acid (300mg, 2.17 mmol) and concentrated sulfuric acid (1.3 mL) were added. Tothe resulting mixture on an ice bath, sodium nitrite (149 mg, 2.16 mmol)dissolved in concentrated sulfuric acid (1.6 mL) was added dropwise, andthen the resulting mixture was stirred for 1 hour. The reaction solutionwas added to ice water, the resulting mixture was vigorously stirred,and the produced solid was collected by filtration. The obtained solidwas dried under reduced pressure at 60° C. for 1 hour to obtain thetitle compound (166 mg, 55%) as pale yellow crystals. 1H NMR (DMSO-ds,400 MHz): δ 7.80 (d, 1H, J=3.7 Hz), 7.64 (d, 1H, J=3.7 Hz)

Example 24 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 mol), and 3-oxo-3,4-dihydropyrazine-2-carboxylic acid (20 mg,0.14 mmol) synthesized in Reference Example 4 were reacted in the samemanner as that of Example 1, except that HOAt (17 mg, 0.13 mmol) wasused instead of triethylamine, WSC (24 mg, 0.13 mmol) was used insteadof HATU, and as the solvent, DMF was used instead of THF. To thereaction solution, a 1.4 N solution of ammonia in methanol was added toterminate the reaction, then the reaction solution was extracted withchloroform, and the organic layer was washed with saturated aqueousammonium chloride, and then with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to preparative TLC using methanol and chloroform(concentration, 20%) as the developing solvent to obtain the titlecompound (5.9 mg, 22%) as pale yellow amorphous substance.

Example 25 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 μmol), and2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (20 mg, 0.13mmol) were reacted in the same manner as that of Example 1, except thatHOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg,0.13 mmol) was used instead of HATU, and as the solvent, DMF was usedinstead of THF. To the reaction solution, a 1.4 N solution of ammonia inmethanol was added to terminate the reaction, and then the reactionsolution was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland chloroform (concentration gradient, 5 to 30%) as the elutionsolvent. In order to eliminate impurities, the obtained compound wassuspended in chloroform and aqueous ammonia, and then collected byfiltration to obtain the title compound (2.5 mg, 9%) as weakly brownamorphous substance.

Reference Example 5 Synthesis of1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

To a 30-mL round bottom flask, 6-oxo-1,6-dihydropyridine-2-carboxylicacid (129 mg, 925 μmol) and 1,1-diethoxy-N,N-dimethylmethaneamine (1.5mL) were added, and the resulting mixture was stirred at 100° C. for 2hours. The reaction solution was cooled to room temperature, and thenconcentrated under reduced pressure. The residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 20%) as the elution solvent to obtainethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 58%) ascolorless oily substance.

To a 50-mL round bottom flask, ethyl1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 533 mol)obtained above was added, and dissolved in ethanol (3 mL), then 5 Naqueous sodium hydroxide (200 μL, 1.0 mmol) was added to the solution,and the resulting mixture was stirred at 55° C. for 2 hours. Thereaction solution was left to cool to room temperature, then made acidicwith 5 N hydrochloric acid (400 μL, 2.0 mmol), and then concentratedunder reduced pressure. Ethanol (3 mL) was added to the residue, and theresulting mixture was concentrated under reduced pressure. The residuewas suspended in ethanol (3 mL), then the insoluble substance wasseparated by filtration, and the filtrate was concentrated under reducedpressure to obtain the title compound (48 mg, 54%) as colorlesscrystalline solid.

¹H NMR (DMSO-d₆, 400 MHz): δ 7.41 (dd, 1H, J=9.2, 6.0 Hz), 6.65 (d, 1H,J=6.4 Hz), 6.53 (d, 1H, J=8.7 Hz), 4.06 (q, 2H, J=6.9 Hz), 1.17 (t, 3H,J=6.9 Hz)

Example 26 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(32 mg, 92 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid(33 mg, 0.19 mmol) synthesized in Reference Example 5, triethylamine (70μL, 0.50 mmol), and HATU (136 mg, 0.36 mmol) were reacted. To thereaction solution, a 2 N solution of ammonia in methanol was added toterminate the reaction, and then the reaction solution was concentratedunder reduced pressure. The residue was suspended in 6% aqueous ammonia,then the suspension was extracted with ethyl acetate, and the organiclayer was dried over anhydrous magnesium sulfate. The insolublesubstance was separated by filtration, and then the filtrate wasconcentrated under reduced pressure. The obtained residue was subjectedto column chromatography (aminosilica gel, 8 g) using methanol andchloroform (concentration gradient, 0 to 20%) as the elution solvent.The obtained compound was dissolved in methanol, and powdered by addingtert-butyl methyl ether to the solution to obtain the title compound (35mg, 76%) as white solid.

Example 27 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one

(1S,3aR,5aS,6R,11bR,11cS)-10-((tert-Butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole(30 mg, 65 μmol), and 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20mg, 0.14 mmol) were reacted in the same manner as that of Example 1,except that HOAt (19 mg, 0.14 mmol) was used instead of triethylamine,WSC (27 mg, 0.14 mmol) was used instead of HATU, and as the solvent, DMFwas used instead of THF. The residue was suspended in water, and thenthe suspension was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 10%) as the elution solvent.

To a 100-mL round bottom flask, the solid obtained above, methanol (2mL), and aqueous ammonia were added, and the resulting mixture wasstirred at room temperature for 3 days. The reaction solution wasconcentrated, and then the residue was suspended in chloroform. Then,the insoluble substance was separated by filtration, and the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to preparative TLC using methanol and chloroform(concentration, 20%) as the developing solvent to obtain the titlecompound (1.7 mg, 6%) as white amorphous substance.

Reference Example 6 Synthesis of1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

To 2-oxo-2H-pyran-5-carboxylic acid (200 mg, 1.43 mmol) and DMAP (17.5mg, 143 μmol) dissolved in dichloromethane (3.3 mL) and THF (3.3 mL),WSC (274 mg, 1.43 mmol) and benzyl alcohol (148 μL, 1.43 mmol) wereadded, and the resulting mixture was stirred at room temperature for 2hours. To the reaction solution, water was added, the insolublesubstance was separated by filtration, and then the reaction solutionwas extracted with hexane. The organic layer was washed with saturatedaqueous sodium hydrogen carbonate. The combined organic layers weredried over anhydrous sodium sulfate, then the insoluble substance wasseparated by filtration, and the filtrate was concentrated under reducedpressure. The obtained residue was dissolved in methanol (10 mL)together with ethylamine hydrochloride (112 mg, 1.37 mmol), andtriethylamine (520 μL, 3.73 mmol) was added to the solution, followed bystirring the resulting mixture at room temperature for 16 hours. Afterthe reaction, the reaction mixture was concentrated under reducedpressure, and saturated aqueous sodium hydrogen carbonate was added tothe obtained residue. The resulting mixture was extracted withchloroform, and the organic layer was washed with saturated brine. Thecombined organic layers were dried over anhydrous sodium sulfate, thenthe insoluble substance was separated by filtration, and the filtratewas concentrated under reduced pressure. The residue was subjected tosilica gel column chromatography (10 g) using ethyl acetate and hexane(concentration gradient, 10 to 60%) as the elution solvent to obtainbenzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (126 mg, 34% for2 steps) as pale yellow amorphous substance.

Benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate obtained abovewas dissolved in methanol (2 mL) and ethyl acetate (2 mL), and 10%palladium/carbon was added to the solution, followed by stirring theresulting mixture at room temperature for 2 hours under a hydrogenatmosphere. After the reaction, the insoluble substance was removed byfiltration through Celite, and the obtained solution was concentrated toobtain the title compound (73 mg, 89%) as pale yellow amorphoussubstance.

¹H NMR (CH₃OD, 400 MHz): δ 8.43 (d, 1H, J=2.3 Hz), 7.95 (dd, 1H, J=9.6,2.3 Hz), 6.51 (d, 1H, J=9.6 Hz), 4.07 (q, 2H, J=7.3 Hz), 1.34 (t, 3H,J=7.3 Hz)

Example 28 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(15 mg, 43 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid(16 mg, 94 μmol) synthesized in Reference Example 6,diisopropylethylamine (37 μL, 0.21 mmol), and HATU (36 mg, 94 μmol) werereacted in the same manner as that of Example 1, except that THF alonewas used as the solvent. To the reaction solution, a 1.4 N solution ofammonia in methanol was added to terminate the reaction, and then thereaction solution was concentrated under reduced pressure. The residuewas suspended in saturated aqueous sodium hydrogen carbonate, and thenthe suspension was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, the insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The obtained residue was subjected to columnchromatography (silica gel, 10 g) using methanol and chloroform(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (13.3 mg, 62%) as white amorphous substance.

Example 29 Synthesis of2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide hydrochloride

To a 50-mL round bottom flask,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide (79 mg, 0.17 mmol) synthesized in Example 1 was added, anddissolved in ethanol (2 mL), then 2 N hydrochloric acid (1 mL) was addedto the solution, and the obtained solution was concentrated underreduced pressure. The obtained residue was dried at 80° C. for 18 hoursunder reduced pressure to obtain the title compound (85 mg, 99%) aswhite amorphous substance.

Example 30 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-onehydrochloride

To a 50-mL round bottom flask,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one(44 mg, 93 μmol) synthesized in Example 3 was added, and dissolved in 2N hydrochloric acid (2 mL), and the obtained solution was concentratedunder reduced pressure. The obtained residue was dried at 100° C. for 18hours under reduced pressure to obtain the title compound (40 mg, 84%)as yellow solid.

Example 31 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,3-((1S,3aR,5aS,6R,11bR,1cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one(26 mg, 54 μmol) synthesized in Example 6, and ethyl acetate were added.The resulting mixture was extracted with 1 N hydrochloric acid, and theaqueous layer was concentrated under reduced pressure. The obtainedresidue was dried at 60° C. for 1 hour under reduced pressure to obtainthe title compound (23 mg, 83%) as pale yellow amorphous substance.

Example 32 Synthesis of3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-onesynthesized in Example 8, and ethyl acetate were added. The resultingmixture was extracted with 1 N hydrochloric acid, and the aqueous layerwas concentrated under reduced pressure. The obtained residue was driedunder reduced pressure to obtain the title compound (11 mg, 39% for 2steps from Example 8) as pale yellow amorphous substance.

Example 33 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one(31 mg, 64 μmol) synthesized in Example 9, and ethyl acetate were added.The resulting mixture was extracted with 1 N hydrochloric acid, and theaqueous layer was concentrated under reduced pressure. The obtainedresidue was dried at 60° C. for 2 hours under reduced pressure to obtainthe title compound (22 mg, 67%) as pale yellow amorphous substance.

Example 34 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-onehydrochloride

To a 10-mL test tube,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one(33 mg, 67 μmol) synthesized in Example 10, and ethyl acetate wereadded. The resulting mixture was extracted with 1 N hydrochloric acid,and the aqueous layer was concentrated under reduced pressure. Theobtained residue was dried at 60° C. for 2 hours under reduced pressureto obtain the title compound (33 mg, 94%) as weakly brown amorphoussubstance.

TABLE 1 Deuterated solvent used for NMR Example measurement NMR data MS1 DMSO-d6 9.07 (br s, 1H), 6.21-8.27 (m, 1H), 7.29-7.44 (m, 3H),6.50-6.59 (m, 1H), 472.21 6.37-6.36 (m, 2H), 4.33 (br s, 0.5H), 3.36 (brs, 0.5H), 2.71-3.45 (m, M + H 9H), 2.09-2.30 (m, 2H), 1.72-1.91 (m, 2H),1.31-1.61 (m, 2H), 0.93-1.09 (m, 3H), 0.61-0.79 (m, 2H), 0.31-0.46 (m,2H), −0.30-0.07 (m, 2H). 2 CD3OD 6.36 (d, 1.4H, J = 7.3 Hz), 6.32 (d,0.6H, J = 7.3 Hz), 7.66 (d, 1.4H, 472.19 J = 6.9 Hz), 7.54-7.58 (m,0.6H), 6.96-7.05 (m, 1H), 6.53-6.69 (m, 2H), M + H 4.66-4.70 (m, 0.7H),4.15-4.20 (m, 0.3H), 3.43-3.81 (m, 2H), 3.01-3.32 (m, 7H), 1.95-2.05 (m,2H), 1.77-1.86 (m, 2H), 1.33-1.67 (m, 2H), 1.43- 1.50 (m, 3H), 0.85-1.00(m, 2H), 0.52-0.65 (m, 2H), 0.17-0.31 (m, 2H). 3 DMSO-d6 11.65 (br s,0.6H), 11.50 (br s, 0.4H), 9.06 (br s, 1H), 7.34-7.42 (m, 2 472.19 H),.6.89 (d, 0.7H, J = 8.2 Hz), 6.84 (d, 0.3H, J = 7.8 Hz), 6.40-8.55 M + H(m, 2H), 6.18 (s, 0.7H, J = 6.9 Hz), 6.13 (s, 0.3H, J = 6.9 Hz),4.29-4.33 (m, 0.7H), 3.95-4.08 (m, 0.6H), 3.79-3.84 (m, 0.3H), 3.54-3.61(m, 1H), 2.63-3.44 (m, 7.4H), 2.22-2.31 (m, 1H), 2.12-2.19 (m, 1H),1.74-1.90 (m, 2H), 1.49-1.59 (m, 1H), 1.27-1.40 (m, 1.7H), 0.90-1.14 (m,2.3H), 0.69-0.75 (m, 1H), 0.54-0.64 (m, 1H), 0.38-0.42 (m, 2H),−0.01-0.05 (m, 2 H). 4 CD3OD 5.46-5.48 (m, 1H), 6.37 (d, 0.7H, J = 7.3Hz), 6.33 (d, 0.3H, J = 6.9 Hz), 472.16 7.52-7.71 (m, 2H), 6.92-7.02 (m,1H), 6.52-6.68 (m, 2H), 4.64-4.69 M + H (m, 0.6H), 4.11-4.19 (m, 0.6H),3.59-3.64 (m, 1H), 3.43-3.46 (m, 0.4H), 2.92-3.39 (m, 7.4H), 1.96-2.05(m, 2H), 1.07-1.65 (m, 7H), 0.82-0.97 (m, 2H), 0.46-0.65 (m, 2H),0.10-0.30 (m, 2H). 5 DMSO-d6 11.70 (br s, 1H), 9.03 (br s, 1H),7.47-7.67 (m, 2H), 6.87-6.88 (m, 1H), 6.47-6.54 472.19 (m, 2H),6.26-6.28 (m, 1H), 3.63-4.53 (m, 3H), 3.16 (t, 1H, J = 12.8 Hz), M + H2.65-3.02 (m, 2.5H), 2.75-2.82 (m, 2.5H), 2.46-2.52 (m, 1H), 2.28 (dd,1H, J = 12.8, 5.5 Hz), 2.16 (dd, 1H, J = 12.8, 6.4 Hz), 1.74-1.91 (m,2H), 1.38-1.60 (m, 2H), 1.11-1.20 (m, 2H), 0.90-0.89 (m, 1H), 0.66-0.77(m, 2H), 0.35-0.42 (m, 2H), −0.02-0.06 (m, 2H). 6 CDC13 7.49 (dd, 0.7H,J = 6.9, 1.8 Hz), 7.46 (dd, 0.3H, J = 6.9, 1.8 Hz), 7.33-7.39 (m, 1H),6.80 (d, 0.7H, J = 8.2 Hz), 6.89 (d, 0.3H, J = 8.2 Hz), 6.58-6.74 (m,2H), 6.22 (t, 6.7H, J = 6.9 Hz), 6.20 (t, 0.3H, J = 6.9 Hz), 4.62-4.72(m, 0.7H), 4.11-4.21 (m, 0.6H), 2.67-3.80 (m, 1H), 3.58 (t, 2.1H), 3.55(s, 0.9H), 3.48-3.61 (m, 1H), 3.22-3.36 (m, 1H), 2.72-3.19 (m, 5H),2.47-2.64 (m, 0.7H), 2.21-2.42 (m, 1.7H), 1.80-2.13 (m, 1.7H), 1.35-1.77(m, 2.4H), 0.95-1.34 (m, 3.2H), 0.33-0.94 (m, 2H), 0.36-0.55 (m, 2H),0.01-0.19 (m, 2H). 7 CD3OD 7.61 (dd, 0.7H, J = 8.7 Hz), 7.53 (dd, 0.3H,J = 9.2, 6.9 Hz), 6.95 (d, 0.7H, 472.2  J = 8.2 Hz), 6.91 (d, 0.3H, J =9.2 Hz), 6.46-6.63 (m, 4H), 4.62 (t, 0.7 M + H H, J = 6.9 Hz), 4.31 (t,0.3H, J = 6.9 Hz), 4.03 (m, 0.1H), 3.87 (m, 0.7H), 3.70 (d, 0.7H, J =11.5 Hz), 3.59 (d, 0.3H, J = 12.4 Hz), 3.25-3.38 (m, 2H), 3.08-3.13 (m,2H), 2.84-3.01 (m, 2H), 2.56 (dd, 1H, J = 11.5, 4.6 Hz), 2.28- 2.34 (m,2H), 1.89-2.09 (m, 2H), 1.67-1.41 (m, 1H), 1.40-1.57 (m, 2H), 1.06- 1.26(m, 2H), 0.77-0.93 (m, 2H), 0.41-0.50 (m, 2H), 0.05-0.13 (m, 2H).

TABLE 2 Deuterated solvent used for NMR Example measurement NMR data MS8 CDC13 12.15 (br s, 1H), 8.20 (br s, 1H), 7.54 (d, 0.5H, J = 5.0 Hz),7.53 (d, 0.5H, J = 5.0 Hz), 6.83-6.94 (m, 1H), 6.72 (d, 0.5H, J = 2.3Hz), 6.51- 6.63 (m, 1.5H), 6.13 (d, 0.5H, J = 7.3 Hz), 6.07 (d, 0.5H, J= 6.9 Hz), 4.57-4.68 (m, 0.5H), 4.14-4.33 (m, 1H), 3.71-3.86 (m, 1H),3.46-3.60 (m, 0.5H), 3.20-3.34 (m, 1H), 2.66-3.17 (m, 5H), 2.45-2.60 (m,1H), 0.69- 2.42 (m, 14H), 0.38-0.52 (m, 2H), 0.02-0.14 (m, 2H). 9 CDC137.85 (s, 0.7H), 7.69 (s, 0.3H), 7.61 (d, 0.7H, J = 8.2 Hz), 7.44 (d,0.3H, J = 8.7 Hz), 6.86-6.98 (m, 1H), 6.47-6.67 (m, 3H), 4.56-4.78 (m,0.7H), 4.10-4.35 (m, 0.6H), 3.66-3.87 (m, 2H), 3.69 (s, 2.1H), 3.65 (s,0.9H), 3.25-3.45 (m, 1H), 2.67-3.21 (m, 5H), 2.48-2.65 (m, 0.7H),2.20-2.43 (m, 1.7H), 1.64-2.12 (m, 2.8H), 0.72-1.50 (m, 6.5H), 0.38-0.56(m, 2H), 0.03-0.19 (m, 2H). 10 DMSO-d6 9.09 (s, 0.7H), 9.07 (s, 0.3H),7.43 (dd, 0.7H, J = 9.2, 6.9 Hz), 7.31- 486.21 7.40 (m, 0.3H), 6.93 (d,0.7H, J = 8.7 Hz), 6.87 (d, 0.3H, J = 7.8 Hz). M + H 6.20-6.61 (m, 4H),3.57-4.49 (m, 2H), 3.32 (s, 0.9H), 3.29 (s, 2.1H), 2.44-3.48 (m, 8H),2.25-2.34 (m, 1H), 2.14-2.23 (m, 1H), 1.74-1.99 (m, 2H), 1.63-1.68 (m,1H), 1.30-1.60 (m, 2H), 0.05-1.25 (m, 2H), 0.62-0.81 (m, 2H), 0.36-0.48(m, 2H), 0.06-0.10 (m, 2H). 11 DMSO-d6 11.70 (br s, 1H), 9.07 (s, 1H),7.42 (d, 0.6H, J = 6.4 Hz), 7.37 (d, 0.4 472.23 H, J = 6.0 Hz), 6.93 (d,0.5H, J = 8.2 Hz), 6.88 (d, 0.4H, J = 8.2 Hz), M + H 6.45-6.58 (m, 2H),6.30 (s, 0.6H), 6.24 (s, 0.4H), 6.13 (d, 0.6H, J = 6.9 Hz), 6.08 (d,0.4H, J = 6.4 Hz), 4.39-4.45 (m, 0.6H), 4.04-4.07 (m, 0.4H), 3.94-3.89(m, 0.4H), 3.60-3.65 (m, 0.6H), 2.98-3.48 (m, 5H), 2.46- 2.91 (m, 3H),2.26-2.34 (m, 1H), 2.16-2.22 (m, 1H), 1.76-1.94 (m, 2H), 1.11-1.63 (m,4H), 0.96-1.03 (m, 1H), 0.66-0.78 (m, 2H), 0.41-0.43 (m, 2H), 0.03-0.10(m, 2H). 12 CD3OD 7.64 (s, 1H), 6.96 (d, 0.8H, J = 8.7 Hz), 6.93 (d,0.2H, J = 8.3 Hz), 489.19 6.61-6.67 (m, 2H), 2.81-5.14 (m, 10H),2.51-2.62 (m, 1H), 2.29-2.39 (m, M + H 2H), 1.87-2.16 (m, 2H), 1.66-1.80(m, 0.8H), 1.38-1.60 (m, 1.2H), 1.06- 1.32 (m, 3H), 0.74-0.95 (m, 1H),0.40-0.56 (m, 2H), 0.03-0.20 (m, 2H). 13 DMSO-d6 11.45-11.66 (m, 1H),9.00-9.19 (m, 1H), 7.48-7.78 (m, 2H), 6.92 (d, 0.7 472.22 H, J = 8.7Hz), 6.87 (d, 0.3H, J = 8.3 Hz), 6.39-6.64 (m, 2H), 6.16 (d, M + H 0.7H,J = 7.3 Hz), 6.12 (d, 0.3H, J = 6.9 Hz), 4.25-4.40 (m, 0.7H), 3.97-4.09(m, 0.3H), 2.41-3.92 (m, 9H), 2.10-2.37 (m, 2H), 1.73-2.00 (m, 2H),0.53-1.69 (m, 7H), 0.34-0.50 (m, 2H), −0.04-0.15 (m, 2H). 14 DMSO-d610.84 (br s, 1H), 9.10 (s, 0.7H), 9.06 (s, 0.3H), 8.08-8.39 (m, 1H),6.39- 472.22 7.05 (m, 5H), 4.45-4.65 (m, 1H), 3.68-4.00 (m, 1H),2.44-3.61 (m, 8H), M + H 2.12-2.37 (m, 2H), 1.74-2.01 (m, 2H), 0.58-1.69(m, 7H), 0.38-0.50 (m, 2H), 0.00-0.14 (m, 2H).

TABLE 3 Deuterated solvent used for NMR Example measurement NMR data MS15 CDC13 7.30-7.40 (m, 1H), 6.89-6.99 (m, 1H), 6.52-6.69 (m, 3H),6.18-6.26 (m, 486.23 1H), 4.60-4.73 (m, 0.5H), 4.09-4.33 (m, 1H),3.67-3.76 (m, 0.5H) 3.49-3.61 M + H (m, 4H), 3.26-3.44 (m, 0.5H),2.71-3.16 (m, 4.5H), 0.71-2.66 (m, 13H), 0.39-0.56 (m, 2H), 0.04-0.17(m, 2H). 16 DMSO-d6 9.07 (br s, 0.7H), 9.05 (br s, 0.3H), 7.61-7.68 (m,1H), 6.67-6.93 (m, 2H), 473.22 6.48-6.60 (m, 2H), 4.56-4.39 (m, 0.3H),4.46-4.52 (m, 0.7H), 4.06 (q, M + H 0.8H, J = 5.0 Hz), 3.95-4.02 (m,1H), 3.82-3.84 (m, 0.7H), 2.50-2.52 (m, 7H), 2.27-2.33 (m, 1H),2.17-2.22 (m, 1H), 1.50-1.94 (m, 2H), 1.59-1.64 (m, 1H), 0.98-1.41 (m,5H), 0.69-0.76 (m, 1H), 0.41-0.43 (m, 2H), 0.02- 0.09 (m, 2H). 17DMSO-d6 9.11 (br s, 1H), 7.30-7.39 (m, 1H), 7.30-7.36 (m, 2H), 7.20-7.23(m, 1H), 522.26 6.94 (d, 0.7H, J = 8.2 Hz), 6.53 (d, 0.3H, J = 7.3 Hz),6.38-6.62 (m, 3 M + H H), 4.50-4.57 (m, 1H), 3.40-3.62 (m, 4H),3.14-3.24 (m, 1H), 2.74-3.03 (m, 4H), 2.52-2.56 (m, 1H), 2.25-2.35 (m,1H), 2.15-2.32 (m, 1H), 1.77- 1.95 (m, 2H), 1.41-1.55 (m, 2H), 0.95-1.05(m, 2H), 0.70-0.81 (m, 2H), 0.35- 0.44 (m, 2H), 0.02-0.09 (m, 2H). 18CD3OD 7.89-8.12 (m, 2H), 6.99 (d, 0.2H, J = 7.6 Hz), 6.97 (d, 0.8H, J =8.2 Hz), 471.22 6.64 (d, 0.2H, J = 2.8 Hz), 6.60-6.62 (m, 1.8H), 5.61(d, 0.8H, J = 9.6 M + H Hz), 5.57 (d, 0.2H, J = 9.2 Hz), 3.23-5.24 (m,5H), 3.11-3.22 (m, 2H), 2.55-3.00 (m, 2H), 2.54-2.63 (m, 1H), 2.27-2.40(m, 2H), 1.93-2.21 (m, 2H), 1.44-1.87 (m, 2H), 0.74-1.41 (m, 5H),0.42-0.52 (m, 2H), 0.06-0.18 (m, 2H). 19 DMSO-d6 9.10 (s, 0.7H), 9.07(s, 0.8H), 9.20 (d, 0.7H, J = 6.0 Hz), 8.13 (d, 0.3H, 473.25 J = 5.5Hz), 6.87-6.97 (m, 1H), 6.45-6.73 (m, 3H), 6.40 (dd, 0.7H, J = M + H6.0, 2.3 Hz), 6.34 (dd, 0.3H, J = 5.5, 2.3 Hz), 4.24-4.51 (m, 1H),3.87-4.01 (m, 1H), 2.35-3.81 (m, 5H), 2.14-2.33 (m, 2H), 1.73-1.95 (m,2H), 1.53- 1.66 (m, 1H), 1.35-1.49 (m, 1H), 0.63-1.31 (m, 5H), 0.34-0.50(m, 2H), 0.03-0.14 (m, 2H). 20 DMSO-d6 9.09 (s, 1H), 7.67 (d, 0.7H, J =7.6 Hz), 7.63 (d, 0.3H, J = 7.3 Hz), 6.93 486.28 (d, 0.7H, J = 8.2 Hz),6.55 (d, 0.3H, J = 6.2 Hz), 6.55 (d, 0.7H, J = M + H 2.3 Hz), 6.49-6.55(m, 1H), 6.46 (dd, 0.3H, J = 5.2, 2.3 Hz), 6.07-6.14 (m, 1.7H), 6.05(dd, 0.3H, J = 7.6, 2.6 Hz), 4.36-4.44 (m, 0.7H), 3.60-4.23 (m, 0.6H),3.63-3.67 (m, 0.7H), 3.47 (s, 2.1H), 8.44 (s, 0.9H), 2.37-3.54 (m, 5H),2.25-2.35 (m, 1H), 2.18 (dd, 1H, J = 12.4, 6.4 Hz), 1.73-1.96 (m, 2H),1.58-1.67 (m, 1H), 1.30-1.51 (m, 2H), 1.11-1.19 (m, 1H), 0.95- 1.05 (m,1H), 0.61-0.81 (m, 2H), 0.35-0.48 (m, 2H), 0.01-0.11 (m, 2H). 21 DMSO-d69.06-9.13 (m, 1H), 7.94 (s, 0.7H), 7.78-7.91 (m, 1.3H), 6.85-6.95 (m,1H), 473.25 6.60 (s, 0.7H), 6.45-6.57 (m, 1.3H), 4.83-4.95 (m, 0.3H),4.49-4.60 (m, M + H 0.7H), 3.58-4.07 (m, 1.7H), 2.39-3.56 (m, 7.3H),2.15-2.35 (m, 2H), 1.77- 1.99 (m, 2H), 1.52-1.67 (m, 1H), 0.96-1.44 (m,4H), 0.62-0.92 (m, 2H), 0.38-0.45 (m, 2H), 0.01-0.13 (m, 2H).

TABLE 4 Deuterated solvent used for NMR Example measurement NMR data MS22 CDC13 8.14-8.18 (m, 1H), 7.03-7.34 (m, 4H), 6.75-6.86 (m, 2H), 4.68(m, 0.6H), 514.27 4.09-4.20 (m, 1H), 3.62-3.70 (m, 0.4H), 3.29-3.40 (m,0.6H), 2.87-3.13 M + H (m, 6.4H), 2.51-2.56 (m, 1H), 1.85-2.26 (m, 8H),1.58-1.67 (m, 2H), 1.10- 1.24 (m, 2H), 0.67-0.89 (m, 2H), 0.36-0.46 (m,2H), 0.03-0.13 (m, 2 H). 23 CDC13 7.05-7.43 (m, 5H), 6.27-6.68 (m, 2H),4.81-4.84 (m, 0.7H), 4.50-4.53 (m, 456.29 0.3H), 4.27-4.36 (m, 0.3H),4.10 (t, 0.7H, J = 11.0 Hz), 3.84 (d, 0.7H, M + H J = 3.8 Hz), 3.57-3.64(m, 0.3H), 3.34-3.48 (m, 1H), 2.78-3.20 (m, 5H), 2.54-2.61 (m, 1H),2.26-2.36 (m, 2H), 1.87-2.05 (m, 2H), 1.15-1.78 (m, 5H), 0.75-0.93 (m,2H), 0.47 (d, 2H, J = 7.8 Hz), 0.05-0.13 (m, 2H). 24 DMSO-d6 9.10 (s,0.6H), 9.07 (s, 0.4H), 7.19-7.62 (m, 2H), 6.92 (d, 0.6H, J = 8.7 473.27Hz), 6.87 (d, 0.4H, J = 0.2 Hz), 6.66-6.36 (m, 2H), 4.33-4.40 (m, 0.6M + H H), 3.91-3.99 (m, 0.4H), 3.86 (dd, 0.4H, J = 12.8, 8.7 Hz), 3.59(dd, 0.6H, J = 10.5, 8.2 Hz), 2.38-3.52 (m, 8H), 2.14-2.34 (m, 2H),1.73-1.95 (m, 2H), 1.61-1.70 (m, 1H), 1.29-1.45 (m, 1H), 0.93-1.27 (m,3H), 0.49- 0.91 (m, 2H), 0.35-0.48 (m, 2H), −0.01-0.12 (m, 2H). 25DMSO-d6 8.96-9.68 (m, 2H), 6.91 (d, 0.6H, J = 8.2 Hz), 6.88 (d, 0.4H, J= 8.2 489.26 Hz), 6.58 (d, 0.6H, J = 6.3 Hz), 6.48-6.54 (m, 1H), 6.45(dd, 0.4H, J = M + H 8.2, 2.3 Hz), 4.88-5.19 (m, 1H), 4.38-4.44 (m,0.4H), 4.28-4.36 (m, 0.6 H), 3.70-3.82 (m, 1H), 2.39-3.61 (m, 8H),2.24-2.34 (m, 1H), 2.14-2.23 (m, 1H), 1.73-1.99 (m, 2H), 1.48-1.66 (m,1H), 0.92-1.45 (m, 4H), 0.56- 0.82 (m, 2H), 0.33-0.50 (m, 2H),−0.02-0.14 (m, 2H). 26 DMSO-d6 9.06 (br s, 0.7H), 9.05 (br s, 0.3H),7.30-7.41 (m, 1H), 6.90 (d, 0.7H, J = 500.31 8.2 Hz), 6.84 (d, 0.3H), J= 8.2 Hz), 6.55 (br s, 1H), 6.50 (dd, 1H, M + H J = 8.2, 2.3 Hz),6.22-6.43 (m, 2H), 4.39 (br s, 1H), 3.52-4.14 (m, 4H), 2.90-3.21 (m,4H), 2.70-2.79 (m, 2H), 2.42-2.50 (m, 1H), 2.13-2.29 (m, 2H), 1.72-1.95(m, 3H), 1.53-1.63 (m, 1H), 1.27-1.39 (m, 1H), 0.94-1.18 (m, 5H),0.57-0.80 (m, 2H), 0.38 (d, 2H, J = 7.8 Hz), 0.02 (br s, 2H). 27 DMSO-d69.08 (s, 0.6H), 9.06 (s, 0.4H), 8.22 (s, 0.6H), 8.15 (s, 0.4H) 6.92 (d,0.6H, 473.28 J = 8.2 Hz), 6.88 (d, 0.4H, J = 7.8 Hz), 6.59 (d, 0.6H, J =2.8 Hz), M + H 6.52 (dd, 0.6H, J = 8.2, 2.8 Hz), 6.49 (d, 0.4H, J = 2.3Hz), 6.46 (dd, 0.4H, J = 7.8, 2.3 Hz), 6.40 (s, 0.6H), 6.37 (s, 0.4H),4.30-4.45 (m, 1H), 3.68-3.93 (m, 1H), 2.40-3.65 (m, 8H), 2.14-2.34 (m,2H), 1.74-1.93 (m, 2H), 1.52-1.67 (m, 1H), 0.93-1.44 (m, 3H), 0.51-0.91(m, 3H), 0.36- 0.48 (m, 2H), 0.01-0.10 (m, 2H). 28 CD3OD 8.04 (s, 0.7H),7.92 (s, 0.3H), 7.55-7.73 (m, 1H), 6.91-7.05 (m, 1H), 6.48- 500.31 6.73(m, 3H), 2.57-5.06 (m, 12H), 2.24-2.74 (m, 2H), 1.91-1.86 (m, 1 M + HH), 1.71-1.86 (m, 1H), 1.09-1.67 (m, 8H), 0.77-1.04 (m, 2H), 0.42-0.70(m, 2H), 0.06-0.36 (m, 2H).

TABLE 5 Deuterated solvent used for NMR Example measurement NMR data MS29 DMSO-d6 9.38 (br s, 1H), 8.91 (br s, 0.3H), 8.74 (br s, 0.7H),8.25-8.29 (m, 1H), 472.24 7.35-7.51 (m, 3H), 7.02 (d, 0.7H, J = 8.2 Hz),6.95 (d, 0.3H, J = 8.7 M + H Hz), 6.66-6.70 (m, 1.3H), 6.50-6.57 (m,0.7H), 4.40 (dd, 0.7, J = 6.0, 2.3 Hz) 3.89-4.00 (m, 1.7H), 3.00-3.57(m, 9.6H), 2.87-2.92 (m, 1H), 2.47- 2.57 (m, 1H), 1.91-2.10 (m, 1H),1.64-1.77 (m, 1H), 1.31-1.69 (m, 3 H), 1.10 (br s, 1H), 0.48-0.69 (m,4H), 0.33-0.39 (m, 1H). 30 DMSO-d6 11.82-11.95 (m, 1H), 9.36 (br s, 1H),9.00 (br s, 0.3H), 8.85 (br s, 0.7 472.26 H), 7.35-7.47 (m, 2H), 6.98(d, 0.7H, J = 7.3 Hz), 6.93 (d, 0.3H, J = M + H 7.8 Hz), 6.46-6.67 (m,2H), 6.12-6.21 (m, 1H), 4.29-4.37 (m, 0.7H), 3.95- 4.04 (m, 1H),3.81-3.87 (m, 0.3H), 2.84-3.63 (m, 12H), 1.83-2.00 (m, 1 H), 1.69-1.71(m, 1H), 1.43-1.64 (m, 1H), 1.27-1.38 (m, 2H), 0.95-1.13 (m, 1H),0.33-0.62 (m, 5H). 31 CD3OD 7.68-7.89 (m, 1H), 7.50-7.66 (m, 1H),7.12(d, 0.7H, J = 8.7 Hz), 7.06 486.21 (d, 0.3H, J = 8.2 Hz), 6.61-6.78(m, 2H), 6.45 (t, 0.7H, J = 6.9 Hz), M + H 6.39 (t, 0.3H, J = 6.9 Hz),3.62 (s, 2.1H), 3.60 (s, 0.9H), 3.09-5.35 (m, 10H), 2.86-3.08 (2H, m),2.69-2.86 (m, 1H), 2.07-2.21 (m, 1H), 1.46-1.96 (m, 4.7H), 1.08-1.21 (m,1.3H), 0.68-0.96 (m, 3H), 0.43-0.67 (m, 2H). 32 CD3OD 7.45-7.66 (m, 1H),7.11 (d, 0.7H, J = 8.2 Hz), 7.05 (d, 0.3H, J = 8.7 486.22 Hz), 6.61-6.79(m, 2H), 6.27 (d, 0.7H, J = 6.9 Hz), 6.21 (d, 0.3H, J = M + H 7.3 Hz),3.11-5.00 (m, 10H), 3.02 (dd, 1H, J = 13.3, 7.3 Hz), 2.69-2.94 (m, 2H),2.34 (s, 2.1H), 2.30 (s, 0.9H), 2.05-2.20 (m, 1H), 1.46-1.92 (m, 4.7H),1.06-1.21 (m, 1.3H), 0.70-0.96 (m, 3H), 0.42-0.55 (m, 2H). 33 CD3OD 8.06(s, 0.8H), 7.94 (br s, 0.2H), 7.73 (d, 0.8H, J = 8.7 Hz), 7.55-7.66486.21 (m, 0.2H), 7.02-7.17 (m, 1H), 6.48-6.82 (m, 3H), 3.09-4.98 (m,13H), 3.03 M + H (dd, 1H, J = 13.3, 7.3 Hz), 2.73-2.96 (m, 2H),2.07-2.22 (m, 1H), 1.39- 1.96 (m, 4.8H), 0.90-1.34 (m, 2.2H), 0.70-0.88(m, 2H), 0.42-0.68 (m, 2H). 34 CD3OD 7.58 (dd, 0.7H, J = 9.2, 6.9 Hz),7.46-7.54 (m, 0.3H), 7.13 (d, 0.7H, J = 486.22 8.2 Hz), 7.07 (d, 0.3H, J= 8.7 Hz), 6.66-6.84 (m, 3H), 6.38-6.51 (m, M + H 1H), 3.26-5.96 (m,13H), 2.89-3.11 (m, 2H), 2.70-2.85 (m, 1H), 2.07- 2.22 (m, 1H),1.83-2.01 (m, 1H), 1.33-1.77 (m, 4H), 1.09-1.21 (m, 1H), 0.71-1.04 (m,3H), 0.43-0.67 (m, 2H).

Reference Example 7-1 Synthesis of 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carboxylate

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carboxylate(972.7 mg, 2.00 mmol) synthesized according to the method described inWO2014/136305, Example 34, (1) was added, and dissolved in methylenechloride (20 mL). The reaction solution was cooled to 0° C., then a 1 Msolution of boron tribromide in methylene chloride (6 mL) was added tothe reaction solution with vigorous stirring, and then the resultingmixture was stirred for 1 hour with warming to room temperature.

To the reaction solution, saturated aqueous sodium hydrogen carbonate(30 mL) was added, and then the resulting mixture was extracted withchloroform (20 mL×3). The combined organic layers were dried overanhydrous sodium sulfate, then the insoluble substance was separated byfiltration, and the filtrate was concentrated under reduced pressure toobtain the title compound (1.04 g, >100%) as white foam-like substance.The crude product was used as it was for the following reaction withoutany further purification.

Reference Example 7-2 Synthesis of 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carboxylate

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carboxylate(1.04 g) synthesized inReference Example 7-1 was added, and dissolved inTHF (20 mL). To the obtained solution, triethylamine (2.79 mL, 20 mmol)and trifluoroacetic anhydride (1.41 mL, 10 mmol) were added, and theresulting mixture was stirred at room temperature for 1 hour. Thereaction solution was concentrated under reduced pressure. The residuewas diluted with saturated aqueous sodium hydrogen carbonate (50 mL),and then extracted with ethyl acetate (30 mL×2). The combined organiclayers were dried over anhydrous sodium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure to obtain the title compound (1.46 g, >100%) aswhite foam-like substance. The crude product was used as it was for thefollowing reaction without any further purification.

Reference Example 7-3 Synthesis of2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-14-yl)ethan-1-one

To a 100-mL recovery flask, 2,2,2-trichloroethyl(1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carboxylate(1.46 g) synthesized in Reference Example 7-2 was added, and dissolvedin acetic acid (25 mL). To the obtained solution, zinc powder (1.31 g,20 mmol) was added, and the resulting mixture was stirred at roomtemperature for 2 hours. The reaction solution was filtered throughCelite to remove excessive zinc powder. The filtrate was concentratedunder reduced pressure, and then azeotroped with toluene. The residuewas diluted with saturated aqueous sodium hydrogen carbonate (30 mL),and then extracted with chloroform (30 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, then the insolublesubstance was separated by filtration, and the filtrate was concentratedunder reduced pressure. The obtained residue was subjected to columnchromatography (aminosilica gel, 16 g) using ethyl acetate and methanol(concentration gradient, 0 to 30%) as the elution solvent to obtain thetitle compound (215 mg, total yield of 27% for 3 steps) as pale yellowfoam-like substance.

¹H NMR CDCl₃: 6.96-7.06 (m, 1H), 6.64-6.72 (m, 1H), 6.52-6.58 (m, 1H),5.90 (br s, 1H), 4.90 (d, 0.5H, J=6.8 Hz), 4.34 (dd, 0.5H, J=6.5, 13.8Hz), 4.18-4.24 (m, 0.5H), 2.72-3.81 (m, 8.5H), 2.21-2.45 (m, 1H),1.46-2.00 (m, 3H), 0.99-1.43 (m, 4H)

Reference Example 8-1 Synthesis of ethyl3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate

This compound was synthesized according to the method described inWO2011/090935.

To a 500-mL recovery flask, a 20% solution of sodium ethoxide in ethanol(60 mL) and ethyl 2-(ethoxymethylene)malonate (10.5 mL, 524 mmol) wereadded, and the resulting mixture was stirred at room temperature for 10minutes. To the obtained mixture, hydrazine monohydrate (5.1 mL, 104mmol) was added, the resulting mixture was stirred at 80° C. for 18hours with heating, and then the obtained yellow suspension was cooledto 0° C. To the reaction solution vigorously stirred, 1 N hydrochloricacid (180 mL) was slowly added at the same temperature to obtain ayellow solution. To the obtained solution, ethyl acetate (150 mL) wasadded, and the resulting mixture was stirred at room temperature for 1hour. The organic layer was separated, and then the aqueous layer wasextracted with ethyl acetate (100 mL×2). The combined organic layerswere dried over anhydrous sodium sulfate, and the insoluble substancewas separated by filtration. The filtrate was concentrated under reducedpressure, and the obtained residue was crystallized by using ethylacetate and hexane to obtain the title compound (2.82 g, 35%) as yellowcrystals (mixture of tautomers). MS ES M−H=155

Reference Example 8-2 Synthesis of3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid

To a 50-mL round bottom flask, ethyl3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (200 mg, 1.28 mmol),iodomethane (397 μL, 6.40 mmol), and DMF (5 mL) were added, sodiumhydride (60%, dispersed in liquid paraffin, 256 mg, 6.40 mmol) was addedto the mixture, and the resulting mixture was stirred at roomtemperature for 22 hours. Under ice cooling, water was added to thereaction solution, and the resulting mixture was extracted three timeswith ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate, then the insoluble substance was separated byfiltration, and the filtrate was concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (25 g)using ethyl acetate and hexane (concentration gradient, 5 to 60%) as theelution solvent to obtain ethyl3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 22%) as whitesolid.

To a 50-mL round bottom flask, ethyl3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 0.279 mmol)obtained above was added, and dissolved in ethanol (1 mL), then 5 Naqueous sodium hydroxide (0.5 mL, 2.50 mmol) was added to the solution,and the resulting mixture was stirred at room temperature for 3 days. Tothe reaction solution, a 1 N hydrochloric acid (2.7 mL) was added, andthe resulting mixture was concentrated under reduced pressure. Theobtained residue was dissolved in THF, the insoluble substance wasseparated by filtration using Celite, and the filtrate was concentratedunder reduced pressure to obtain the title compound (43 mg, 100%) aswhite powder.

¹H NMR DMSO-d₆: 11.91 (br s, 1H), 7.99 (a, 1H), 3.80 (s, 3H), 3.69 (s,3H)

Example 35 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

To a 10 m-L test tube,2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-14-yl)ethan-1-one(54 mg, 136 μmol) synthesized in Reference Example 7-3,6-oxo-1,6-dihydropyridine-2-carboxylic acid (67 mg, 0.48 mmol), and HATU(197 mg, 0.52 mmol) were added, and suspended in THF (2 mL), thentriethylamine (100 μL, 0.72 mmol) and DMA (100 μL) were added to thesuspension, and the resulting mixture was stirred at room temperaturefor 1.5 hours. To the reaction mixture, ethanolamine (100 μL) andmethanol (2 mL) were added, and the resulting mixture was stirred at thesame temperature for 1 hour. The reaction solution was concentratedunder reduced pressure, the obtained residue was dissolved in chloroform(30 mL), and the solution was washed with 6% aqueous ammonia (10 mL×3).The combined aqueous layers were extracted with chloroform (20 mL). Thecombined organic layers were dried over anhydrous magnesium sulfate, theinsoluble substance was separated by filtration, and then the filtratewas concentrated under reduced pressure. The obtained residue wassubjected to column chromatography (aminosilica gel, 16 g) usingmethanol and chloroform (concentration gradient, 10 to 30%) as theelution solvent to obtain6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one(M+H=514.26) as white foam-like substance.

6-((1S,3aR,5aS,6R,11bR,11cS)-10-Hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-oneobtained above was dissolved in methanol (5 mL) in a 100-mL recoveryflask, sodium borohydride (124 mg, 3.26 mmol) was added to the solution,and the resulting mixture was stirred at room temperature for 2 hours.The reaction solution was concentrated under reduced pressure, theresidue was suspended in 6% aqueous ammonia (20 mL), and the suspensionwas washed with chloroform (20 mL×2). The aqueous layer was concentratedunder reduced pressure, and the residue was subjected to columnchromatography (aminosilica gel, 12 g) using methanol and chloroform(concentration gradient, 10 to 30%) as the elution solvent, and therebypurified to obtain a mixture of6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,and the title compound,6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one.

The mixture obtained above was dissolved in concentrated aqueous ammonia(3 mL) in a 50-mL recovery flask, and the solution was heated at 80° C.for 18 hours in a tube sealed with a rubber stopper. The reactionmixture was concentrated under reduced pressure, and the residue wassubjected to column chromatography (aminosilica gel, 7 g) using methanoland chloroform (concentration gradient, 10 to 50%) as the elutionsolvent. The obtained crude product was powdered by using methanol (0.2mL) and t-butyl methyl ether (3 mL) to obtain the title compound (23 mg,41%).

¹H NMR DMSO-d₆: 9.08 (s, 1H), 7.53 (dd, 0.7H, J=6.9, 8.7 Hz), 7.47 (dd,0.3H, J=7.3, 9.2 Hz), 6.92 (d, 0.7H, J=8.2 Hz), 6.87 (d, 0.3H, J=7.8Hz), 6.39-6.58 (m, 4H), 4.42-4.45 (m, 0.7H), 4.13-4.17 (m, 0.3H),3.89-3.94 (m, 0.3H), 3.71-3.76 (m, 0.7H), 3.61 (d, 0.7H, J=11.0 Hz),3.45-3.48 (m, 0.3H), 3.15-3.27 (m, 1H), 2.80-3.09 (m, 5H), 2.64-2.73 (m,1H), 2.13-2.44 (m, 2H), 1.63-1.70 (m, 1H), 1.25-1.59 (m, 2H), 1.12-1.15(d, 1H, J=11.0 Hz), 1.01-1.07 (m, 1H), 0.88-0.94 (m, 1H), 0.66-0.74 (m,1H)

Example 36 Synthesis of4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(30 mg, 86 mol), 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (29mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72mg, 0.19 mmol) were reacted in the same manner as that of Example 1,except that THF (2 mL) alone was used as the solvent. To the reactionsolution, a 1.4 N solution of ammonia in methanol was added to terminatethe reaction, and then the reaction solution was concentrated underreduced pressure. The residue was suspended in saturated aqueous sodiumhydrogen carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (silica gel, 10 g) using methanoland ethyl acetate (concentration gradient, 0 to 30%) as the elutionsolvent, and thereby purified to obtain((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone(33.3 mg, 80%) as pale yellow amorphous substance.

¹H NMR CD₃OD: 7.69 (s, 0.7H), 7.55 (s, 0.3H), 6.90-6.96 (m, 1H), 6.63(d, 0.7H, J=2.8 Hz), 6.53-6.58 (m, 1.3H), 2.78-5.02 (m, 8H), 3.90 (s,3H), 3.73 (s, 2.1H), 3.68 (s, 0.9H), 2.53-2.57 (m, 1H), 2.31-2.33 (m,2H), 1.90-2.09 (m, 2H), 1.66-1.76 (m, 1H), 1.51-0.78 (m, 7H), 0.45-0.48(m, 2H), 0.09-0.12 (m, 2H)

To a 30-mL round bottom flask,((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone(15 mg, 31 μmol) obtained above was added, and dissolved in methylenechloride (1 mL). A 1.0 M solution of boron tribromide in methylenechloride (153 μL, 0.15 mmol) was added to the solution under icecooling, and the resulting mixture was stirred at room temperature for 1hour. A 1.4 N solution of ammonia in methanol was added to terminate thereaction, and then the reaction solution was concentrated under reducedpressure. The residue was suspended in saturated aqueous sodium hydrogencarbonate, and then the suspension was extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, the insolublesubstance was separated by filtration, and then the filtrate wasconcentrated under reduced pressure. The obtained residue was subjectedto preparative TLC using methanol containing aqueous ammonia andchloroform (concentration, 10%) as the developing solvent to obtain thetitle compound (10.6 mg, 73%) as pale yellow amorphous substance.

¹H NMR DMSO-de: 11.47 (s, 0.1H), 11.37 (s, 0.9H), 9.11 (s, 1H), 8.09 (s,0.9H), 7.48 (s, 0.1H), 6.94 (d, 1H, J=8.2 Hz), 6.60 (d, 1H, J=2.3 Hz),6.64 (dd, 1H, J=8.2, 2.3 Hz), 4.33-4.50 (m, 1H), 2.50-4.07 (m, 12H),2.19-2.34 (m, 2H), 1.80-2.00 (m, 2H), 1.58-1.65 (m, 1H), 0.70-1.43 (m,6H), 0.38-0.53 (m, 2H), 0.02-0.16 (m, 2H)

Example 37 Synthesis of5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(20 mg, 57 mol), 5-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid(22 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU(72 mg, 0.13 mmol) were reacted in the same manner as that of Example 1,except that THF (1 mL) alone was used as the solvent. To the reactionsolution, a 1.4 N solution of ammonia in methanol was added to terminatethe reaction, and then the reaction solution was concentrated underreduced pressure. The residue was suspended in saturated aqueous sodiumhydrogen carbonate, and then the suspension was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,the insoluble substance was separated by filtration, and then thefiltrate was concentrated under reduced pressure. The obtained residuewas subjected to column chromatography (aminosilica gel, 8 g) usingmethanol and ethyl acetate (concentration gradient, 0 to 80%) as theelution solvent, and thereby purified to obtain the title compound (11.6mg, 40%) as brown amorphous substance.

¹H NMR DMSO-d₆: 11.99 (br s, 1H), 9.06 (br s, 1H), 7.68 (s, 0.7H), 7.59(s, 0.3H), 7.48 (d, 1H, J=2.3 Hz), 6.89 (d, 0.7H, J=8.2 Hz), 6.85 (d,0.3H, J=8.2 Hz), 6.40-6.56 (m, 2H), 4.25-4.32 (m, 0.7H), 3.93-3.98 (m,0.3H), 3.78-3.84 (m, 0.3H), 2.11-3.62 (m, 10.7H), 1.68-1.91 (m, 2H),1.48-1.63 (m, 1H), 0.87-1.46 (m, 4H), 0.50-0.79 (m, 2H), 0.29-0.47 (m,2H), 0.06-0.12 (m, 2H)

Example 38 Synthesis of5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

In the same manner as that of Example 1,(1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indol-10-ol(35 mg, 98 μmol),1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid(35 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (145 mg,0.38 mmol) were reacted, then to the reaction solution, a 2 N solutionof ammonia in methanol was added to terminate the reaction, and then thereaction solution was concentrated under reduced pressure. The residuewas suspended in 6% aqueous ammonia (20 mL), and the suspension wasextracted with ethyl acetate (15 mL×2). The combined organic layers werewashed with saturated brine (10 mL), and then dried over anhydrousmagnesium sulfate. The insoluble substance was separated by filtration,and then the filtrate was concentrated under reduced pressure. Theresidue was subjected to column chromatography (aminosilica gel, 10 g)using methanol and ethyl acetate (concentration gradient, 0 to 30%) asthe elution solvent, and thereby purified. The obtained syrup-likesubstance was dissolved in methanol (0.2 mL), then powdered by addingt-butyl methyl ether (3 mL) to the solution, and collected by filtrationto obtain the title compound (39 mg, 76%) as white powder.

¹H NMR CD₃OD: 7.82 (s, 1H), 6.92-6.98 (m, 1H), 6.52-6.65 (m, 2H),4.53-4.62 (m, 1H), 4.02-4.18 (m, 1H), 3.50-3.80 (m, 2H), 3.42 (s, 2H),3.37 (s, 1H), 3.33 (s, 2H), 3.31 (s, 1H), 2.81-3.18 (m, 5H), 2.57-2.59(m, 1H), 2.30-2.38 (m, 2H), 1.93-2.09 (m, 2H), 1.67-1.78 (m, 1H),1.43-1.59 (m, 2H), 1.10-1.29 (m, 2H), 0.81-0.95 (m, 2H), 0.44-0.53 (m,2H), 0.08-0.17 (m, 2H)

Example 39 Synthesis of6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

The experiment was performed in the same manner as that of Example 1.

(1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole(82 mg, 0.23 mmol) prepared according to the method described inWO2013/035833, Example 67, triethylamine (200 μL, 1.43 mmol), and HATU(167 mg, 0.44 mmol) were reacted. Then, to the reaction solution,ethanolamine (200 μL) and methanol (1 mL) were added to terminate thereaction, and then the reaction mixture was diluted with ethyl acetate(50 mL), and washed with 6% aqueous ammonia (50 mL). The aqueous layerwas extracted with chloroform (30 mL×2), and the combined organic layerswere dried over anhydrous sodium sulfate. The insoluble substance wasseparated by filtration, and then the filtrate was concentrated underreduced pressure. The residue was subjected to column chromatography(aminosilica gel, 7 g) using methanol and ethyl acetate (concentrationgradient, 10 to 50%) as the elution solvent, and thereby purified. Theobtained syrup-like substance was dissolved in methanol (0.2 mL), andthen powdered by adding t-butyl methyl ether (3 mL) to the solution. Theobtained powder was dried at 100° C. for 16 hours under reduced pressureto obtain the title compound (87 mg, 100%) as white amorphoussubstance-like substance.

¹H NMR DMSO-d₆: 7.5 (br s, 1H), 6.97-7.03 (m, 1H), 6.45-6.73 (m, 4H),4.40-4.45 (m, 0.7H), 3.84-3.89 (m, 0.3H), 3.69 (s, 3H), 3.55-3.62 (m,1H), 2.95-3.22 (m, 4H), 2.79-2.84 (m, 2H), 2.13-2.62 (m, 41H), 1.79-1.87(m, 2H), 1.26-1.60 (m, 3H), 0.99-1.14 (m, 3H), 0.70-0.74 (m, 1H),0.54-0.61 (m, 1H), 0.39-0.40 (m, 2H), 0.00-0.07 (m, 2H)

Example 40 Opioid Receptor Function Test

The functional activities of the compounds provided by the presentinvention on the μ, δ, and κ opioid receptors were investigated.

Method:

The test was performed by using Lance Ultra cAMP Kit (PerkinElmer)according to a method predetermined for the kit. In the evaluation ofthe agonistic activity, CHO cells expressing each of the human opioidreceptors (δ, μ, and κ, accession numbers and catalog numbers arementioned below) and 10 μM of each test compound were reacted for 30minutes in an assay buffer (1×HBSS, 1 M HEPES, pH 7.4, 250 mM IBMX(isobutylmethylxanthine), 7.5% BSA) in the presence of forskolin.Subsequently, the cAMP detection reagent included in the kit was added,and 1 hour afterward, time-resolved fluorescence measurement wasperformed by using the EnVision plate reader (PerkinElmer). The testcompounds and the control drugs (δ: SNC80, μ: DAMGO, κ: U-69593) wereevaluated in a concentration range of 10⁻¹² to 10⁻⁵ M, a dose-responsecurve of each test compound was obtained from the fluorescence values at665 nm, and EC₅₀ value and the E_(max) value were calculated. TheE_(max) value was calculated as a ratio of the maximum reaction of thetest compound to the maximum reaction of each control drug, which istaken as 100%.

SNC80:

-   (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide

DAMGO:

-   [D-Ala²,N-MePhe⁴,Gly-ol]enkephalin

U-69593:

-   (+)-(5a,7a,8)-N-Methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide

Accession Numbers and Catalogue Numbers

δ: Catalog No. CT4607, Accession No. NM_000911.2μ: Catalog No. CT4605, Accession No. NM_000914κ: Catalog No. CT4606, Accession No. NM_000912

(ChanTest Corporation)

TABLE 6 δ receptor EC₅₀ μ receptor κ receptor value Emax EC₅₀ value EmaxEC₅₀ value Emax Example (nM) (%) (nM) (%) (nM) (%) 1 <3 88 NO 8.3* >1 123 <3 98 >1 20 <1 15 4 <3 86 NO 5.5* >10  27 5 <3 81 >1 9.7 <1 20 6 <397 >10  7.7 NO 3.2* 7 <3 99 >1 10 NO −0.9* 8 <3 70 >1 8.6 <1 21 9 <3 74<1 15 <1 14 10 <3 74 NO 6.0* NO −0.7* 11 <3 76 >1 11 NO −2.5* 14 <395 >1 8.1 NO 5.7 16 <3 92 >1 19 <1 29 19 <3 91 >1 19 NO 0.6* 28 <3 92 >116 <1 18 31 <3 97 >10  7.7 NO 3.2* 32 <3 70 >1 8.6 <1 21 N.C.: Since themaximum reaction was not reached at the maximum concentration (10 μM),the ED₅₀ value was not calculated. *Since the maximum reaction was notreached at the maximum concentration, a reaction rate at the maximumconcentration is mentioned as a reference value.

As shown in Table 6, it was confirmed that the compounds of the presentinvention have potent agonistic activities for the opioid δ receptor,but do not have agonistic activity or have only very weak agonisticactivity for the and x receptors.

Example 41 Mouse Elevated Plus Maze Test (Test Method)

For the test, 5 to 6 weeks old C57BL/6N male mice were used. On a plusmaze apparatus consisting of a wall-less running route (open arm, width6 cm, length 30 cm) and a running route with a wall (closed arm, width 6cm, length 30 cm, height of wall 15 cm), and having a height of 40 cm, amouse was put so as to be directed to the running route with a wall, andallowed to spontaneously enter into the plus maze. Each test substancewas dissolved in saline or 0.005 N HCl in saline, and subcutaneouslyadministered on the back 30 minutes before the start of the test. At thetime of the start of the test, video recording with a video camera wasstarted, the time at which the mouse entered into the plus maze isconsidered to be the start of the test, and exploratory behavior wasrecorded for 5 minutes. On the basis of the video image, staying timesin the running routes were determined, and wall-less running routestaying time ratio (%) was calculated.

(Test Results)

As shown in FIGS. 1 and 2, from this experiment, it was found thatsubcutaneous administrations of the compound 1 (the compound describedin Example 1) and the compound 7 (the compound described in Example 7)at a dose of 3 mg/kg and 10 mg/kg, respectively, significantly increasedthe wall-less running route staying time ratio and thus it was confirmedthat they exhibit anxiolytic-like effects. The compound 3 (the compounddescribed in Example 3), the compound 9 (the compound described inExample 9), and the compound 10 (the compound described in Example 10)also showed a tendency of increasing the wall-less running route stayingtime ratio (FIGS. 3 to 5).

Example 42 Rat Elevated Plus Maze Test

Anxiolytic effects of the compounds provided by the present inventionwere investigated by the rat elevated plus maze test.

(Test Method)

For the test, 7 to 9 weeks old Wistar male rats were used. On a plusmaze apparatus consisting of a wall-less running route (width 10 cm,length 50 cm) and a running route with a wall (width 10 cm, length 50cm, height of wall 30 cm), and having a height of 50 cm, a rat was putso as to be directed to the running route with a wall, and allowed tospontaneously enter into the plus maze, and exploratory behavior wasobserved for 5 minutes. Each test substance was dissolved in a 4.5%aqueous solution of cyclodextrin, and orally administered 2 hours beforethe start of the test. The test data were automatically analyzed byusing video image action analysis software (Smart3.0, PanLab S.L.,PanLab), and wall-less running route staying time ratio (%) wascalculated.

(Test Results)

As shown in FIG. 6, from this experiment, it was found that oraladministration of 3 mg/kg of each of the compound 7 (the compounddescribed in Example 7), the compound 3 (the compound described inExample 3), and the compound 10 (the compound described in Example 10)significantly increased the wall-less running route staying time ratio,and thus it was confirmed that they exhibit anxiolytic-like effects.

Example 43

hERG (Human Ether-a-go-go-Related Gene) Potassium Channel InhibitionTest

(Test Method)

The test was performed with Port-a-Patch automatic patch clump apparatus(Nanion Technologies) using hERG channel-stably expressing CHO cells(purchased from Channelopathy Foundation). The membrane potential of thecells was maintained at −80 mV, then there were applied a depolarizationpulse at +20 mV for 1.5 seconds, and a following test pulse at −50 mVfor 1.5 seconds at a frequency of 1 time per 10 seconds, and the hERGcurrent was confirmed as a tail current induced by the test pulse. Thetest compound was dissolved in an extracellular fluid (137 mM NaCl, 4 mMKCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mM D(+)-glucose, 10 mM HEPES, pH 7.4),and the solution was refluxed at room temperature for 5 minutes. Theinhibition ratio was obtained from the ratio of the tail current valueobserved after the compound was applied based on the tail current valueobserved before the compound was applied, which was taken as 100%. Forthe test, we used cells that showed a peak tail current value notsmaller than 300 pA, tail current run-down smaller than 10% of theinitial current value, and leak current smaller than 200 pA.

(Test Results)

The test results are shown in Table 7.

In the table, the compounds 1, 3, 7, 9, and 10 are the compoundsdescribed in Examples 1, 3, 7, 9, and 10, respectively.

As clearly seen from the results shown in Table 7, all the testcompounds showed only weak inhibitory effects.

On the other hand, it was revealed that the compounds disclosed inWO2013/35833 (Patent document 4) include those having potent hERGinhibitory effects.

TABLE 7 hERG channel Example Concentration inhibitory action Compound 110 μM <50% Compound 3 10 μM <50% Compound 7 10 μM <50% Compound 9 10 μM<50% Compound 10 10 μM <50% Comparative compound 1 10 μM >50%Comparative compound 2 10 μM >50% Comparative compound 1: Compound ofWO2013/35833, Example 93 (compound 104) Comparative compound 2: Compoundof WO2013/35833, Example 205 (compound 267)

Example 44 Hyperemotional Reaction Inhibition Test Using OlfactoryBulbectomized (OBX) Rat (Test Method)

According to the method of Saitoh et al. (Saitoh A, Yamada M, Yamada M,Takahashi K, Yamaguchi K, Murasawa H, Nakatani A, Tatsumi Y, Hirose N,and Kamei J: Antidepressant-like effects of the delta-opioid receptoragonist SNC80((+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide)in an olfactory bulbectomized rat model, Brain Res., 2008,1208:160-169), OBX rats were prepared by extracting the rat olfactorybulbs, and then breeding the rats in an isolated circumstance.Hyperemotional reaction was evaluated on the day 14 after the surgicaloperation and before the division into groups, and 2 hours after theadministration on the days 1, 4, 7, 10, and 14 of the administrationperiod according to the hyperemotional reaction evaluation criteriaprepared by Gomita et al. (Gomita et al., Behavioral pharmacological andelectroencephalographical studies of7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H:)-dione(Clobazam), Folia Pharmacologica Japonica, 82, 267 (1983)). The drug wassubcutaneously administered once a day continuously over 14 days. As apositive control drug, fluoxetine, which is a selective serotoninreuptake inhibitor (SSRI), was used. As the solvent, a 1% cyclodextrin(CD) was used.

(Test Results)

Administration of 0.1 mg/kg of the test substance (the compounddescribed in Example 7 mentioned above) significantly reduced thehyperemotional reactions of the OBX rats from the day 4 of theadministration period compared with the solvent administration group,and restored the condition even to a level comparable to that of therats of the sham surgery group on the day 7 of the administrationperiod. Administration of 1 mg/kg of the test substance significantlyreduced the hyperemotional reactions of the OBX rats from the day 1 ofthe administration period compared with the solvent administrationgroup, and restored the condition even to a level comparable to that ofthe rats of the sham surgery group on the day 4 of the administrationperiod. These effects were maintained until the day 14. On the otherhand, administration of fluoxetine at 10 mg/kg significantly reduced thehyperemotional reactions of the OBX rats on the day 14 of theadministration period compared with the solvent administration group.

In the above investigation, it was demonstrated that the test substancemight show antidepressant-like effect even with single administration,unlike SSRI. Therefore, it was suggested that the test substance showedthe antidepressant-like effect earlier compared with SSRI. It was alsosuggested that tolerance may not be induced for the antidepressant-likeeffect of the test substance.

Example 45 Reserpine-Induced Parkinson's Disease Model Mouse (TestMethod)

ICR male mice (5 weeks old, Japan SLC) were obtained, and used after anacclimation period (5 to 12 days).

PD model was prepared with reference to the report of Hille et al. (Exp.Neurol., 2001, 172:189). It was prepared by intraperitoneallyadministering reserpine (5 mg/kg) 18 to 24 hours before the start of thetest. The test was performed by subcutaneously administering a testcompound to each mouse on the day of the test, immediately putting themouse into a cage for monitoring locomotor activity, and measuring themigration distance over 60 minutes.

(Test Results)

Since administration of the test substance (the compound described inExample 7 mentioned above) at 10 mg/kg significantly increasedexploratory behavior, and also, a tendency of increase of standing upbehavior was found, although it was not significant (P=0.16),Parkinson's disease-curing effect of the test substance was suggested.

Example 46 Evaluation Using Rat Cerebral Infarction-Induced OveractiveBladder Model (Test Method)

A transient middle cerebral artery occlusion model was prepared by using8 weeks old SD male rats under isoflurane inhalation anesthesia. On thenext day, the cervix was slightly cut open again under the isofluraneinhalation anesthesia, and a catheter for administration was fixed inthe jugular vein, and led to the back. A cystometry operation was alsoperformed, and the other end of a cannula inserted into the bladder wasled to the back, and connected to a cannula swivel.

On the day 4 after the cerebral ischemia operation, cystometry wasperformed under no anesthesia and with no restraint. Intravesicalpressure was measured for the stable period, then a medium wasintravenously administered, and the value of the pressure was measuredover about 30 minutes as a value before test substance administration.Then, the test substance was cumulatively and intravenously administeredfrom the lowest dose at intervals of about 30 minutes, and the value wasmeasured for about 30 minutes after each administration. For the ratsdetermined to show pollakiuria (urination interval was 10 minutes orshorter) in the measurement before the administration, staticintravesical pressure, pressure at the time of urination, urinationinterval, and single urination amount were measured at each time point.

(Test Results)

The measurement results are shown in Table 8.

As clearly seen from the results shown in Table 8, the test substance(the compound described in Example 7 mentioned above) did not affect thestatic intravesical pressure and pressure at the time of urination atall the doses. On the other hand, the urination interval and singleurination amount showed a dose-dependently increasing tendency, andtherefore pollakiuria-improving effect of the test substance wassuggested.

TABLE 8 n Vehicle 0.01 mg/kg 0.1 mg/kg Static pressure 5 10.6 ± 1.3  9.5± 1.3 9.6 ± 1.1 (mmHg) Pressure at the 5 41.4 ± 10.0 42.9 ± 10.7 42.8 ±9.7  time of urination (mmHg) Urination interval 5 384.4 ± 63.2  450.7 ±76.9  547.4 ± 122.5 (sec) Single urination 5 0.288 ± 0.061 0.310 ± 0.0680.403 ± 0.129 amount (g) Mean ± S.E. (n = 5)

Example 47 Metabolic Stability Test (Test Method)

Human hepatic microsomes and a test substance were reacted for a certainperiod of time (0 to 60 minutes). The test substance, which was notmetabolized in the reaction sample, was measured, and remaining ratiowas calculated. The test substance-remaining ratio at the time when thereaction time is 0 hour is taken as 100%. The remaining ratio afterincubation was plotted against time as a log-linear plot to obtain aregression line (y=100e^(−kt), k=inclination of straight line: clearancerate constant), and metabolic clearance CL_(int) (mL/min/kg) wascalculated by using the following equation.

CL _(int) *=k(−min)×52.5 (mg MS protein/g liver)×26 (g liver/kg)/MSprotein (mg MS protein/mL)

*: Davies, B. and Morris T., Physiological parameters in laboratoryanimals and humans, Pharm. Res., 10(7):1093-1095, 1993

(Test Results)

The test results are shown in Table 9.

TABLE 9 Comparative Example 1 Example 7 Example 10 Example 16 compound 1CL_(int) 19 5.6 13 18 25

Comparative Compound 1: WO2013/35833, Example 93 (Compound 104)

As clearly seen from the results shown in Table 9, it was revealed thatthe compounds of the present invention have superior metabolicstability. On the other hand, it was revealed that the compoundsdescribed in WO2013/35833 (Patent document 4) include those showing badmetabolic stability.

1. A pharmaceutical composition comprising a compound represented by thefollowing formula (I), a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof:

wherein R¹ represents hydrogen; C₁₋₁₀ alkyl; C₆₋₁₀ aryl; C₂₋₆ alkenyl;cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms; aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; C₃₋₆ cycloalkyl; or heteroarylalkyl where the heteroarylmoiety contains 1 to 4 heteroatoms selected from N, O, and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbonatoms, R² represents heterocyclic ring containing 1 to 4 heteroatomsselected from N, O, and S and at least one carbon atom asring-constituting atoms, containing at least one set of adjacentring-constituting atoms bound by a double bond, and further substitutedwith at least one oxo group, R² binds to Y via a carbon atom as aring-constituting atom of R², R³, R⁴, and R⁵, which are the same ordifferent, represent hydrogen; hydroxy; halogen; cyano; carbamoyl; C₁₋₆alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyloxy; nitro; amino; C₁₋₈ alkylamino;C₆₋₁₀ arylamino; or acylamino where the acyl moiety has 2 to 6 carbonatoms, R^(6a) and R^(6b), which are the same or different, representhydrogen; fluorine; or hydroxy, or R^(6a) and R^(6b) combine together torepresent ═O, R⁷ and R⁸, which are the same or different, representhydrogen; fluorine; or hydroxy, R⁹ and R¹⁰, which are the same ordifferent, represent hydrogen; C₁₋₆ alkyl; C₆₋₁₀ aryl; heteroarylcontaining 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms; aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms;heteroarylalkyl where the heteroaryl moiety contains 1 to 4 heteroatomsselected from N, O and S as ring-constituting atoms, and the alkylenemoiety has 1 to 5 carbon atoms; cycloalkylalkyl where the cycloalkylmoiety has 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; or C₂₋₆ alkenyl, X represents O or CH₂, and Y representsC(═O), provided that the C₁₋₁₀ alkyl as R¹; the alkylene moiety andcycloalkyl moiety of the cycloalkylalkyl where the cycloalkyl moiety has3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms asR¹; the alkylene moiety of the aralkyl where the aryl moiety has 6 to 10carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms as R¹; andthe alkylene moiety of the heteroarylalkyl where the heteroaryl moietycontains 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atomsas R¹ may be substituted with at least one substituent selected from 1to 6 halogens; hydroxy; C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl; C₁₋₆alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy moiety has 1 to 6carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has 1 to6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; alkylsulfonyl where the alkyl moiety has 1 to 6 carbonatoms; aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6carbon atoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms;C₁₋₆ alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where thearyl moiety has 6 to 10 carbon atoms, the C₆₋₁₀ aryl as R¹; the arylmoiety of the aralkyl where the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 5 carbon atoms as R¹; the aryl moietyof the C₆₋₁₀ aryloxy as R³, R⁴, or R⁵; the aryl moiety of the C₆₋₁₀arylamino as R³, R⁴, or R⁵; the C₆₋₁₀ aryl as R⁹ or R¹⁰; the heteroarylcontaining 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms as R⁹ or R¹⁰; the aryl moiety of the aralkylwhere the aryl moiety has 6 to 10 carbon atoms, and the alkylene moietyhas 1 to 5 carbon atoms as R⁹ or R¹⁰; and the heteroaryl moiety of theheteroarylalkyl where the heteroaryl moiety contains 1 to 4 heteroatomsselected from N, O and S as ring-constituting atoms, and the alkylenemoiety has 1 to 5 carbon atoms as R⁹ or R¹⁰ may be substituted with atleast one substituent selected from C₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₄alkanoyloxy; hydroxy; alkoxycarbonyl where the alkoxy moiety has 1 to 6carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl moiety has 1 to6 carbon atoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6carbon atoms; halogen; nitro; cyano; C₁₋₆ alkyl substituted with 1 to 3halogens; C₁₋₆ alkoxy substituted with 1 to 3 halogens; phenyl;heteroaryl containing 1 to 4 heteroatoms selected from N, O and S asring-constituting atoms; phenoxy; phenylalkyl where the alkyl has 1 to 3carbon atoms; and methylenedioxy, the heterocyclic ring as R² may have,besides the oxo group, the substituents that the C₆₋₁₀ aryl as R¹mentioned above may have, and when R¹ is C₁₋₁₀ alkyl, it may besubstituted with NR¹¹R¹², where R¹¹ and R¹², which are the same ordifferent, represent hydrogen; C₁₋₁₀ alkyl; or aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms; or R¹¹, R¹², the nitrogen atom to which R¹¹ and R¹² bind,and optionally, 1 or 2 heteroatoms may combine together to form a 5- to7-membered ring, and the alkylene moiety of the aralkyl where the arylmoiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹ may be substituted with at least one substituentselected from phenyl, and C₁₋₆ alkyl substituted with 1 to 3 halogens.2. The pharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R¹ is C₁₋₁₀alkyl; cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms; or aralkyl wherethe aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.
 3. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R¹ is cycloalkylalkyl where the cycloalkyl moietyhas 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbonatoms.
 4. The pharmaceutical composition comprising the compound, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to claim 1,wherein R¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆ alkylsubstituted with 1 to 6 halogens; or C₂₋₆ alkyl substituted with C₁₋₆alkoxy.
 5. The pharmaceutical composition comprising the compound, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to claim 1,wherein R¹ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl,2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl.
 6. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² is a 5-to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selectedfrom N, O, and S and at least one carbon atom as ring-constitutingatoms, containing at least one set of adjacent ring-constituting atomsbound by a double bond, and further substituted with at least one oxogroup; or a heterocyclic ring consisting of the foregoing heterocyclicring and a benzene ring condensed thereto.
 7. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is pyridine 1-oxide, which maybe substituted with 1 to 4 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.8. The pharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridine 1-oxide.
 9. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyridin-2(1H)-one, which may be substitutedwith 1 to 4 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.
 10. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is pyridin-2(1H)-one; 1-(C₁₋₆alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆ alkyl)pyridin-2(1H)-one.
 11. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridin-4(1H)-one, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.
 12. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyridin-4(1H)-one, or 1-(C₁₋₆alkyl)pyridin-4(1H)-one.
 13. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyridazin-3(2H)-one, which may be substitutedwith 1 to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.
 14. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to 1, wherein R² is pyridazin-3(2H)-one.
 15. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according claim 1, wherein R² ispyrazin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl and C₁₋₁₀ alkyl substituted with 1 to 3fluorine atoms.
 16. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyrazin-2(1H)-one.
 17. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is 4H-pyran-4-one, or2H-pyran-2-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.
 18. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is 4H-pyran-4-one, or 2H-pyran-2-one.
 19. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² isquinolin-2(1H)-one, which may be substituted with 1 to 3 substituentsselected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms, andunsubstituted C₁₋₁₀ alkyl.
 20. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is quinolin-2(1H)-one.
 21. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is pyrimidin-4(3H)-one, orpyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl.
 22. The pharmaceutical compositioncomprising the compound, a tautomer or stereoisomer of the compound, ora pharmaceutically acceptable salt thereof, or a solvate thereofaccording to claim 1, wherein R² is pyrimidin-4(3H)-one, orpyrimidine-2,4(1H,3H)-dione.
 23. The pharmaceutical compositioncomprising the compound, a tautomer or stereoisomer of the compound, ora pharmaceutically acceptable salt thereof, or a solvate thereofaccording to claim 1, wherein X is CH₂.
 24. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to 1, wherein one of R³ and R⁴ is hydroxy, and theother is hydrogen.
 25. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R³ is halogen; cyano; carbamoyl; C₁₋₆ alkoxy; C₁₋₆alkanoyloxy; amino; or acylamino where the acyl moiety has 2 to 6 carbonatoms, R⁴ is hydrogen or hydroxy, and R⁵ is hydrogen.
 26. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R³ ishydroxy; carbamoyl; or C₁₋₆ alkanoyloxy, R⁴ is hydrogen, and R⁵ ishydrogen.
 27. The pharmaceutical composition comprising the compound, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to claim 1,wherein R³ is hydroxy, R⁴ is hydrogen, and R⁵ is hydrogen.
 28. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein all of R³,R⁴, and R⁵ are hydrogens.
 29. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein all of R^(6a), R^(6b), R⁷, R⁸, R⁹, and R¹⁰ arehydrogens.
 30. The pharmaceutical composition comprising the compoundrepresented by the aforementioned formula (I), a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein: R⁵, R^(6a),R^(6b), R⁷, R⁸, R⁹, and R¹⁰ are hydrogens, R¹ is hydrogen; C₁₋₆ alkyl;C₂₋₆ alkenyl; cycloalkylalkyl where the cycloalkyl moiety has 3 to 6carbon atoms, and the alkylene moiety has 1 to 5 carbon atoms; oraralkyl where the aryl moiety has 6 to 10 carbon atoms, and the alkylenemoiety has 1 to 5 carbon atoms, R² is a 5- to 7-membered heterocyclicring containing 1 to 4 heteroatoms selected from N, O and S and at leastone carbon atom as ring-constituting atoms, containing at least one setof adjacent ring-constituting atoms bound by a double bond, and furthersubstituted with at least one oxo group; or a heterocyclic ringconsisting of the foregoing heterocyclic ring and a benzene ringcondensed thereto, R² binds to Y via a carbon atom of R² as aring-constituting atom, R³ and R⁴, which are the same or different,represent hydrogen; hydroxy; halogen; cyano; carbamoyl; C₁₋₆ alkoxy;C₆₋₁₀ aryloxy; C₁₋₆ alkanoyloxy; amino; or acylamino where the acylmoiety has 2 to 6 carbon atoms, X is CH₂, and Y is C(═O), provided thatthe C₁ alkyl as R¹; the alkylene moiety and cycloalkyl moiety of thecycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms, andthe alkylene moiety has 1 to 5 carbon atoms as R¹; and the alkylenemoiety of the aralkyl where the aryl moiety has 6 to 10 carbon atoms,and the alkylene moiety has 1 to 5 carbon atoms as R¹ may be substitutedwith at least one substituent selected from 1 to 6 halogens; hydroxy;C₁₋₆ alkoxy; C₆₋₁₀ aryloxy; C₁₋₆ alkanoyl; C₁₋₆ alkanoyloxy; carboxyl;alkoxycarbonyl where the alkoxy moiety has 1 to 6 carbon atoms;carbamoyl; alkylcarbamoyl where the alkyl moiety has 1 to 6 carbonatoms; dialkylcarbamoyl where each alkyl moiety has 1 to 6 carbon atoms;alkylsulfonyl where the alkyl moiety has 1 to 6 carbon atoms;aminosulfonyl; alkylsulfinyl where the alkyl moiety has 1 to 6 carbonatoms; alkylthio where the alkyl moiety has 1 to 6 carbon atoms; C₁₋₆alkoxy substituted with 1 to 6 halogens; and arylcarbonyl where the arylmoiety has 6 to 10 carbon atoms, the aryl moiety of the aralkyl wherethe aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms as R¹; and the aryl moiety of the C₆₋₁₀ aryloxy as R³or R⁴ may be substituted with at least one substituent selected fromC₁₋₆ alkyl; C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; hydroxy; alkoxycarbonyl wherethe alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoylwhere the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl whereeach alkyl moiety has 1 to 6 carbon atoms; halogen; nitro; cyano; C₁₋₆alkyl substituted with 1 to 3 halogens; C₁₋₆ alkoxy substituted with 1to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selectedfrom N, O and S as ring-constituting atoms; phenoxy; phenylalkyl wherethe alkyl has 1 to 3 carbon atoms; and methylenedioxy, the heterocyclicring as R² may have, besides the oxo group, at least one of thesubstituents which the aryl moiety of the aralkyl where the aryl moietyhas 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5 carbonatoms as R¹ may have, and the alkylene moiety of the aralkyl where thearyl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 5carbon atoms as R¹ may be substituted with at least one substituentselected from phenyl, and C₁₋₆ alkyl substituted with 1 to 3 halogens.31. The pharmaceutical composition comprising the compound, a tautomeror stereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R¹ is C₁₋₆alkyl; cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbonatoms, and the alkylene moiety has 1 to 5 carbon atoms; or aralkyl wherethe aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1to 5 carbon atoms.
 32. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R¹ is cycloalkylalkyl where the cycloalkyl moietyhas 3 to 6 carbon atoms, and the alkylene moiety has 1 to 5 carbonatoms.
 33. The pharmaceutical composition comprising the compound, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to claim 1,wherein R¹ is C₂₋₆ alkyl substituted with hydroxy; C₁₋₆ alkylsubstituted with 1 to 6 halogens; or C₂₋₆ alkyl substituted with C₁₋₆alkoxy.
 34. The pharmaceutical composition comprising the compound, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof according to claim 1,wherein R¹ is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl,2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl.
 35. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridine 1-oxide, pyridin-2(1H)-one, pyridin-4(1H)-one,pyridazin-3(2H)-one, pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one,quinolin-2(1H)-one, pyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione,which may be substituted with a substituent selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.36. The pharmaceutical composition comprising the compound, a tautomeror stereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridine 1-oxide, which may be substituted with 1 to 4 substituentsselected from C₁₋₁₀ alkyl and C₁₋₁₀ alkyl substituted with 1 to 3fluorine atoms.
 37. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyridine 1-oxide.
 38. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is pyridin-2(1H)-one, which maybe substituted with 1 to 4 substituents selected from C₁₋₁₀ alkyl andC₁₋₁₀ alkyl substituted with 1 to 3 fluorine atoms.
 39. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridin-2(1H)-one; 1-(C₁₋₆ alkyl)pyridin-2(1H)-one; or 6-(C₁₋₆alkyl)pyridin-2(1H)-one.
 40. The pharmaceutical composition comprisingthe compound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyridin-4(1H)-one, which may be substitutedwith 1 to 4 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.
 41. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is pyridin-4(1H)-one, or1-(C₁₋₆ alkyl)pyridin-4(1H)-one.
 42. The pharmaceutical compositioncomprising the compound, a tautomer or stereoisomer of the compound, ora pharmaceutically acceptable salt thereof, or a solvate thereofaccording to claim 1, wherein R² is pyridazin-3(2H)-one, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.43. The pharmaceutical composition comprising the compound, a tautomeror stereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyridazin-3(2H)-one.
 44. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is pyrazin-2(1H)-one, which may be substitutedwith 1 to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.
 45. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R^(Z) is pyrazin-2(1H)-one. 46.The pharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² is4H-pyran-4-one, or 2H-pyran-2-one, which may be substituted with 1 to 3substituents selected from C₁₋₁₀ alkyl substituted with 1 to 3 fluorineatoms, and unsubstituted C₁₋₁₀ alkyl.
 47. The pharmaceutical compositioncomprising the compound, a tautomer or stereoisomer of the compound, ora pharmaceutically acceptable salt thereof, or a solvate thereofaccording to claim 1, wherein R^(Z) is 4H-pyran-4-one, or2H-pyran-2-one.
 48. The pharmaceutical composition comprising thecompound, a tautomer or stereoisomer of the compound, or apharmaceutically acceptable salt thereof, or a solvate thereof accordingto claim 1, wherein R² is quinolin-2(1H)-one, which may be substitutedwith 1 to 3 substituents selected from C₁₋₁₀ alkyl substituted with 1 to3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.
 49. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R² is quinolin-2(1H)-one.
 50. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, which may besubstituted with 1 to 3 substituents selected from C₁₋₁₀ alkylsubstituted with 1 to 3 fluorine atoms, and unsubstituted C₁₋₁₀ alkyl.51. The pharmaceutical composition comprising the compound, a tautomeror stereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R² ispyrimidin-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione.
 52. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein one of R³and R⁴ is hydroxy, and the other is hydrogen.
 53. The pharmaceuticalcomposition comprising the compound, a tautomer or stereoisomer of thecompound, or a pharmaceutically acceptable salt thereof, or a solvatethereof according to claim 1, wherein R³ is halogen; cyano; carbamoyl;C₁₋₆ alkoxy; C₁₋₆ alkanoyloxy; amino; or acylamino where the acyl moietyhas 2 to 6 carbon atoms, and R⁴ is hydrogen or hydroxy.
 54. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R³ ishydroxy; carbamoyl; or C₁₋₆ alkanoyloxy, and R⁴ is hydrogen.
 55. Thepharmaceutical composition comprising the compound, a tautomer orstereoisomer of the compound, or a pharmaceutically acceptable saltthereof, or a solvate thereof according to claim 1, wherein R³ ishydroxy, and R⁴ is hydrogen.
 56. The pharmaceutical compositioncomprising the compound, a tautomer or stereoisomer of the compound, ora pharmaceutically acceptable salt thereof, or a solvate thereofaccording to claim 1, wherein R³ and R⁴ are hydrogens.
 57. Apharmaceutical composition comprising a compound selected from, atautomer or stereoisomer of the compound, or a pharmaceuticallyacceptable salt thereof, or a solvate thereof:2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one,4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-2H-pyran-2-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-4H-pyran-4-one,2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one,5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridine1-oxide,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one,3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one,6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one,and5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphth[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one.58. The pharmaceutical composition according to claim 1, which is fortherapeutic or prophylactic treatment of a pain.
 59. The pharmaceuticalcomposition according to claim 58, wherein the pain is headache.
 60. Thepharmaceutical composition according to claim 59, wherein the headacheis migraine.
 61. The pharmaceutical composition according to claim 58,wherein the pain is fibromuscular pain.
 62. The pharmaceuticalcomposition according to claim 61, which is for therapeutic orprophylactic treatment of depression or anxiety symptom of fibromuscularpain.